- Email: [email protected]
Is intractable epilepsy a tauopathy?
Medical Hypotheses 76 (2011) 897–900
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Is intractable epilepsy a tauopathy? Zhi-Qin Xi a, Xue-Feng Wang a,⇑, Xiao-Fang Shu b, Guo-Jun Chen a, Fei Xiao a, Ji-Jun Sun a, Xi Zhu a a b
Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China Department of Gynaecology and Obstetrics, Central Hospital Mianyang City, Sichuan Province, China
a r t i c l e
i n f o
Article history: Received 22 July 2010 Accepted 3 March 2011
a b s t r a c t Tau exists in neuronal axons and glial cells of the central nervous system and contributes to the maintenance of the unique cell morphology. It functions in axon elongation, cell polarity formation and microtubule stabilization. Aggregates and hyper-phosphorylated tau proteins are classical components of neurofibrillary lesions in numerous neurodegenerative disorders, which are called ‘‘tauopathies’’. Recent studies have demonstrated that tau-associated genes and proteins and tau phosphorylation were abnormal in intractable epilepsy. Therefore, the discovery of the dysfunctional tau in intractable epilepsy opens a new window in the study of central tauopathy. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction Epilepsy, a disorder of recurrent seizures, is a common devastating neurological condition. More than 30 percent of patients with epilepsy have inadequate control of seizures even if treated with various antiepileptic drugs (AEDs) at maximum doses either alone or in combination. Such epileptic cases are referred to as intractable epilepsy (IE) [1,2]. A 2009 consensus proposal by the Task Force of the International League Against Epilepsy (ILAE) Commission defined drugresistant epilepsy as ‘‘a failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as a monotherapy or in combination) to achieve sustained seizure freedom’’ [2]. One half of the patients with medically IE are potential candidates for surgery. The temporal lobe epilepsy, frontal epilepsy, and progressive myoclonic epilepsies tend to be refractory to AED [1–3]. Temporal lobe epilepsy (TLE), especially mesial temporal sclerosis is an example of a surgically remediable syndrome [3]. One of the progressive myoclonic epilepsies, the focal cortical dysplasia (FCD), is the most common malformation of cortical development that undergoes surgical series [4]. Tauopathies result from abnormal tau phosphorylation, abnormal levels of tau, abnormal tau splicing, or mutations in the tau gene. Accumulations of hyper-phosphorylated tau (p-tau) proteins are present in neurons, astrocytes, and oligodendrocytes [5]. One of the properties of the tau protein is its ability to self-assemble into the filamentous structures that are the pathological hallmark of Alzheimer’s disease (AD) and other neurodegenerative disorders ⇑ Corresponding author. Address: Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 1 You Yi Road, Chongqing 400016, China. Tel.: +86 23 89012878; fax: +86 23 68811487. E-mail address: [email protected] (X.-F. Wang). 0306-9877/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.03.003
[6–9]. Neurodegenerative conditions, particularly dementias, AD and Parkinson’ disease (PD), appear more frequently in people with epilepsy [10]. Previous literature has reported higher prevalence ratios (PR) of AD in younger adult epilepsy groups than in older ones (PR 40 vs. 7). Similarly, more epileptic attacks also occur in earlier stage of dementia and cerebral degeneration [11].
Hypothesis AD, PD, focal cortical dysplasia, and aging have manifestations that include epilepsy, tau dysfunctions and a responsiveness to anti-epileptic medications such as valproic acid and zonisamide [10–26]. On the other hand, abnormal tau presents in both human and animal models of epilepsy. We hypothesize that IE is also a tauopathy. This concept should be beneficial for increasing our understanding of epilepsy and other tauopathies and for exploring the essential pathophysiological changes accompanying the epileptic attacks.
Explanatory evidence Evidence suggests that tau is involved in the pathogenesis of IE. Interestingly, all tau-positive neurodegenerative disorders, including AD, PD, and Pick’s disease, are accompanied by recurrent secondary epileptic seizures. However, all tau-negative diseases, such as the frontal dementia of non-AD and non-pick type diseases, are not associated with secondary epileptic seizures [10–15]. For example, studies in humans have reported the prevalence of seizures in dementia and AD varies from 5% to 64% [11], indicating that seizures occur more frequently in these diseases than in the general population, and a younger age is a risk factor for seizures in AD. Patients
898
Z.-Q. Xi et al. / Medical Hypotheses 76 (2011) 897–900
with AD and other types of dementias have a greater risk (5–10 fold) of developing epilepsy compared to age-matched controls [10]. Seizure severity, in terms of symptomatology, frequency, and the responsiveness to antiepileptic drugs, are different in these degenerative disorders. In AD, generalized seizures are common, which usually originates from a partial seizure focus. In addition, complex partial status epilepticus and myoclonus have been reported as later manifestations [15,16,27]. Sixty-three of the 1738 AD patients listed in the Alzheimer Disease Patient Registry (ADPR) and Alzheimer Disease Research Center (ADRC) had epilepsy. Seventy-two percent of the 63 patients had complex partial seizure activity. Seventy-six percent of these patients had an excellent response to the AED therapy. Approximately one-third of these patients had dose-related side effects from an AED [13]. Other similarities between IE, AD, and PD are also found in terms of immunoreactivity for ubiquitin, amyloid b protein [6] b-amyloid precursor protein (APP) [7,28], apolipoprotein E [21–23], and a-synuclein [3]. These proteins are abnormally expressed in IE animal models and patients [3,20–23]. Immunoreactive APP and a-synuclein were elevated in surgically resected human temporal lobe tissue from patients with IE and in the animal pilocarpine model. Apolipoprotein E e4 is associated with several disease-related traits, including the increased risk of late posttraumatic seizures, the earlier onset of TLE, refractory complex partial seizures, reduced memory and verbal learning, and postictal confusion. The apolipoprotein E e3/e4 genotype was more frequently seen in the simple febrile convulsion group than in the complicated febrile convulsion group [21–23]. Most drugs, such as valproic acid, levetiracetam, and zonisamide, can be used to treat these diseases regardless of epilepsy. Valproic acid has been used for the past 10 years to control agitation in dementia [25,26]. Low dose levetiracetam treatment may reduce the observed hyperactivity and improve memory performance among individuals with mild cognitive impairment [26]. For AD, a multicenter, randomized, double-blinded, parallel-treatment, placebo-controlled study in Japan suggested that zonisamide (ZNS), as an add-on treatment, has efficacy in the treatment of motor symptoms in patients with PD. The duration of ‘‘off’’ time was significantly reduced in the ZNS groups vs. placebo, but dyskinesia was not increased in the ZNS groups [29]. Studies support the utility of zonisamide for other symptoms of PD [30]. Levetiracetam, for the treatment of PD patients with moderate-to-severe levodopainduced dyskinesia (LID) on stable dopaminergic therapy, showed mild anti-dyskinetic effects without a worsening of Parkinsonian symptoms or a compromise in levodopa efficacy [31].
Discussion Tau pathological effects in IE A current popularly accepted concept is that abnormal neuronal network formation is involved in intractable epileptogenesis. Morphological rearrangements in the mossy fiber synapses occur after seizures [32]. Research on granule cell hyperexcitability in patients and in numerous animal models of epilepsy has found a recurrent excitatory granule cell network formed by sprouting mossy fiber axons [33–36]. Aberrant axonal sprouting is modulated by a family of molecules called microtubule-associated proteins (MAPs) [37,38]. Studies on seizure semiology and seizure expression in the elderly have shown that complex partial seizures rarely originate in the temporal lobes. In most of these instances, neocortical seizures arrive from fronto-parietal regions and then the neuronal activity could spread into hippocampus [39]. Cellular loss in the hippocampal formation, changes in long-term potentiation maintenance, an alteration in kindling, an increased susceptibility to
status epilepticus, and neuronal damage from stroke are usually seen in the older epilepsy brain. All of these changes can lead to aberrant axonal sprouting [37–40]. Tau proteins belong to the family of MAPs. Six different isoforms of tau are present in the adult human brain [5,35,41]. Phosphorylated tau is the active form of tau. Enzymes capable of modulating tau phosphorylation include glycogen synthase kinase-3b (GSK-3b), cyclin-dependent kinase 5 (CDK5), the mitogen-activated protein kinase (MAPK) family members, and c-Jun NH2-terminal kinases (JNKs) [33,42–44]. The majority of sprouts are tipped by expanded growth cone-like structures that exhibit immunoreactivity for tau, although these cones are generally smaller than developmental growth cones [37]. Neuritic sprouting has been described in the CA1 region of the hippocampus during the early stages of AD and is associated predominantly with tau-immunoreactive neuritic plaques [43,45]. Furthermore, the extent of tau phosphorylation has been particularly associated with dendritic sprouting [45]. Morphologic rearrangements, which may occur after seizures, were studied in the mossy fiber synapses because they have unique morphologic and cytochemical features that allow their identification unambiguously by light and electron microscopy [32]. A majority of research on granule cell hyperexcitability in patients and in numerous animal models of epilepsy has found recurrent excitatory granule cell network formed by sprouted mossy fiber axons [33–36]. Tau exists in the neuronal axons and glial cells of the central nervous system and contributes to axonal elongation, the formation of neuronal polarity, the maintenance of the special morphology of neurons, and the normal assembly of microtubules [35,41]. Tau can be transported to the mossy fibers via axoplasmic flow and induces an abnormal growth of the mossy fibers to sprout and form new synaptic connections. These new connections transform local circuits in the hilus and in the inner molecular layer and establish abnormal excitatory networks between granule cells [46]. Moreover, proliferated nervous processes may establish abnormal synapses with adjacent neurons and contribute to the pathogenesis of IE through synaptic reorganization [41,46]. Animal models of epilepsy have shown that the hyperphosphorylation of MAPs temporally and spatially coincides with sprouting [40,47,48]. In the nucleus amygdala-kindled model of TLE, the distribution of increased MAPs was associated with the hyperplasia and hypertrophy of granular cell dendrites in the hippocampus dentate gyrus [48]. The results of our previous study showed that the up-regulated MAP1A, MAP2, tubulin, and kinesin in epilepsy might have enhanced the interaction of tau and the microtubule, which then led to the aberrant axonal sprouting [49]. The development and progression of IE is a complex multi-step process involving alterations in the expression and function of a variety of different genes. Using gene chips, we analyzed the gene expression profiles from brains of IE patients. We found tau-associated genes, including MAP1A (microtubule-associated protein 1A), MAP2, P38, CDK5, myoglobin 1E (MYO1E), laminin beta 1 (LAMB1), tubulin gamma 1 (TUBG1), casein kinase 2 (alpha 1 polypeptide) (CSNK2A1), glycogen synthase kinase 3b (GSK-3b), and cadherin 18 type 2, were up-regulated in IE, while tubulin delta 1 (TUBD1) and MAP1B were down-regulated [49]. The findings on MAP1A, MAP1B, MAP2, CDK5, MYO1E, and GSK-3b were consistent with those by previously published articles [20,49]. Some new abnormally-expressed genes, such as LAMB1, CSNK2A1, and TUBD1, have never been reported in IE. In animal epilepsy models, the hyperphosphorylation of MAPs temporally and spatially coincide with sprouting. In the nucleus amygdala-kindled model of TLE, the distribution of increased MAPs was associated with the hyperplasia and hypertrophy of granular cell dendrites in the hippocampus dentate gyrus [48]. MAP1A and MAP1B displayed different affinities to tubulin. The elevated MAPs increased their interaction with the microtubule. MAP2 competes
Z.-Q. Xi et al. / Medical Hypotheses 76 (2011) 897–900
with MAP1B for binding to tubulin [50,51]. The longitudinal binding of MAP2/tau proteins to protofilaments leads to microtubule stabilization by bridging the tubulin interfaces [41,52]. However, MAPs also regulate their binding affinity to microtubules by phosphorylation [42,44]. Abnormal tau levels were associated with either acute or remote symptomatic seizures. The presence of elevated cerebrospinal fluid (CSF) tau increases the probability of seizure attacks [53].
899
ing that IE is a true tauopathy. Overall, a better knowledge of how p-tau proteins are aggregated in neurological diseases is essential for the development of future differential diagnosis and therapeutic strategies. These therapies would hopefully find their application in not only IE but also other neurological disorders, in which a dysfunction of tau biology has been identified. Conflict of interest statement
Roles of tau kinases in epilepsy None declared. Tau is defined as a phosphoprotein. Kinases that are capable of phosphorylating tau at specific sites include glycogen synthase kinase 3b (GSK3b), cycline-dependent kinase 5 (CDK5). Tau can also be phosphorylated by protein kinase A (PKA), protein kinase C (PKC), Ca2+/calmodulin kinase II (CamKII) [42–44,54]. Although many kinases modify tau, GSK3b and CDK5 play important roles in the regulation of tau phosphorylation under physiological and pathological conditions. In the central nervous system, GSK-3b is developmentally regulated with peak levels of expression during axogenesis. GSK-3b is present in growing axons, but it is completely excluded from axons at the end of axogenesis [54]. In addition to glycogen synthase, the GSK-3b phosphorylates a number of substrates, including metabolic and signaling proteins, structural proteins, and transcription factors that regulate cell survival [55]. The inhibition of GSK-3b is associated with a reduction in axon growth and a dramatic increase in growth cone size. The over-expression of GSK-3b in the cortex and hippocampus leads to decreased levels of nuclear b-catenin, an increased phosphorylation of tau, neuronal cell death, and reactive astrocytosis [56,57]. Dysfunction of beta-catenin-mediated signaling pathways in mice leads to cortical malformation and an increased seizure susceptibility [58]. Lafora progressive myoclonus epilepsy is caused by defective laforin and is rapidly followed by IE. Laforin is a GSK3 Ser9 phosphatase. The dephosphorylation of GSK3 at Ser9 activates GSK3 resulting in the inhibition of glycogen synthase through phosphorylation at multiple sites [59]. CDK5 is a unique member of the CDK family that is activated by interactions with the regulatory proteins p35 and p39 that are expressed almost exclusively in postmitotic neurons. These proteins are essential for developing appropriate cortical laminar architecture and are implicated in synaptic transmission, synaptic plasticity, and neuronal signaling. Moreover, CDK5 likely plays a role in cellular motility and adhesion, drug addiction [60], and neurodegeneration. Chronic electroconvulsive seizures (ECS) in mice cause an increased phosphorylation of tau followed by an increase in CDK5 catalytic activity [61]. Abnormal CDK5 expression and the aggregation of this protein in focal cortical dysplasia are important causes of refractory epilepsy in humans, suggesting that CDK5 may be involved in this important epileptogenic pathology [54]. Recently, Sen et al. [62] also found hippocampal sclerosis (HS) in chronic medical IE in adults that showed an increased activity of CDK5 and its activator, the p35/p25 complex. Tauopathies are considered as a group of disorders that are the consequence of abnormal tau phosphorylation, abnormal levels of tau, abnormal tau splicing, or mutations in the tau gene. Lines of evidence have supported that tau phosphorylation and associated genes were increased in the IE patients and animal models. Axonal sprouting with hyperphosphorylated tau proteins might be a defining neuropathological characteristic of IE. Thus, we propose that IE is a new subclass of tauopathy. Conclusions The interaction of dysfunctional tau and its associated proteins might be related to the sprouting of neuronal axons in IE, suggest-
Acknowledgments Chongqing Medical Science and Technology Bureau of Research Projects (2009-2-356) and Chongqing Natural Science Fund (X1263-0200190012). References [1] Berg AT, Kelly MM. Defining intractability: comparisons among published definitions. Epilepsia 2006;47(2):431–6. [2] Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc task force of the ILAE commission on therapeutic strategies. Epilepsia 2010;51(6):1069–77. [3] Yang JW, Czech T, Felizardo M, Baumgartner C, Lubec G. Aberrant expression of cytoskeleton proteins in hippocampus from patients with mesial temporal lobe epilepsy. Amino Acids 2006;30(4):477–93. [4] Giulioni M, Martinoni M, Rubboli G, Marucci G, Marliani AF, Battaglia S, et al. Temporo-mesial extraventricular neurocytoma and cortical dysplasia in focal temporal lobe epilepsy. J Clin Neurosci 2011;18(1):147–8. [5] Binder LI, Frankfurter A, Rebhun LI. The distribution of tau in the mammalian central nervous system. J Cell Biol 1985;1:1371–8. [6] Lee VM-Y, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci 2001;24:1121–59. [7] Zhukareva V, Mann D, Pickering-Brown S, Uryu K, Shuck T, Shah K, et al. Sporadic Pick’s disease: a tauopathy characterized by a spectrum of pathological tau isoforms in gray and white matter. Ann Neurol 2002;51:730–9. [8] Lambourne SL, Sellers LA, Bush TG, Choudhury SK, Emson PC, Suh YH, et al. Increased tau phosphorylation on mitogen-activated protein kinase consensus sites and cognitive decline in transgenic models for Alzheimer’s disease and FTDP-17: evidence for distinct molecular processes underlying tau abnormalities. Mol Cell Biol 2005;25(1):278–93. [9] Veeranna Takahide K, Barry B, Odrljin T, Mohan P, Basavarajappa BS, Peterhoff C, et al. Calpain mediates calcium-induced activation of the Erk1, 2 MAPK pathway and cytoskeletal phosphorylation in neurons. Am J Pathol 2004;65:795–805. [10] Mendez M, Lim G. Seizures in elderly patients with dementia: epidemiology and management. Drugs Aging 2003;20(11):791–803. [11] Scarmeas N, Honig LS, Choi H, Cantero J, Brandt J, Blacker D, et al. Seizures in Alzheimer disease: who, when, and how common? Arch Neurol 2009;66(8):992–7. [12] Johannessen LC. Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs 2008;22(1):27–47. [13] Rao SC, Dove G, Cascino GD, Petersen RC. Recurrent seizures in patients with dementia: frequency, seizure-types and treatment outcome. Epilepsy Behav 2009;14(1):118–20. [14] Hommet C, Mondon K, Camus V, De Toffol B, Constans T. Epilepsy and dementia in the elderly. Dement Geriatr Cogn Disord 2008;25:293–300. [15] Mendez MF. Seizures in Alzheimer’s disease: clinicopathologic study. J Geriatr Psychiatry Neurol 1994;7(4):230–3. [16] Sirven JI. Acute and chronic seizures in patients older than 60 years. Mayo Clinic Proc 2001;76(2):175–83. [17] Pantazis G, Altenmueller1 DM, Feil B, Rona S, Kurth C, Rating D, et al. Clinical characteristics in focal cortical dysplasia: a retrospective evaluation in a series of 120 patients. Brain 2006;129(7):1907–16. [18] Leppika IE, Kellyb KM, deToledo-Morrellc L, Patrylod PR, DeLorenzoe1 RJ, Mathernf GW, et al. Basic research in epilepsy and aging. Basic research in epilepsy and aging. Epilepsy Res. 68 (Suppl. 1) 21–37. [19] Cloyda J, Hauserb W, Townec A, Ramsayd R, Mattsone R, Gilliamf F, et al. Epidemiological and medical aspects of epilepsy in the elderly. Epilepsy Res. 68 (Suppl. 1) 39–48. [20] Xiao F, Chen D, Lu Y, Xiao Z, Guan LF, Yuan J, et al. Proteomic analysis of cerebrospinal fluid from patients with idiopathic temporal lobe epilepsy. Brain Res 2009;1255:180–9. [21] Chapin JS, Busch RM, Janigro D, Dougherty M, Tilelli CQ, Lineweaver TT, et al. APOE epsilon4 is associated with postictal confusion in patients with
900
[22]
[23]
[24]
[25] [26] [27]
[28] [29] [30]
[31]
[32] [33]
[34]
[35]
[36] [37]
[38]
[39]
[40]
[41]
[42]
[43]
Z.-Q. Xi et al. / Medical Hypotheses 76 (2011) 897–900 medically refractory temporal lobe epilepsy. Epilepsy Res 2008;81(2-3): 220–4. Gambardella A, Aguglia U, Chifari R, Labate A, Manna I, Serra P, et al. ApoE epsilon4 allele and disease duration affect verbal learning in mild temporal lobe epilepsy. Epilepsia 2005;46(1):110–7. Busch RM, Lineweaver TT, Naugle RI, Kim KH, Gong Y, Tilelli CQ, et al. ApoEepsilon4 is associated with reduced memory in long-standing intractable temporal lobe epilepsy. Neurology 2007;68(6):409–14. Sporis D, Sertic J, Henigsberg N, Mahovic D, Bogdanovic N, Babic T. Association of refractory complex partial seizures with a polymorphism of ApoE genotype. J Cell Mol Med 2005;9(3):698–703. Zhang XZ, Li XJ, Zhang HY. Valproic acid as a promising agent to combat Alzheimer’s disease. Brain Res Bull 2010;15;81(1):3–6. Weiner MF, Womack KB, Martin-Cook K, Svetlik DA, Hynan LS. Levetiracetam for agitated Alzheimer’s disease patients. Int Psychogeriatr 2005;17(2):327–8. Gaitatzis A, Carroll K, Majeed A, Sander WJ. The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia 2004;45(12): 1613–22. Delacourte A, Buée LT. Au pathology: a marker of neurodegenerative disorders. Curr Opin Neurol 2000;13:371–6. Murata M. Zonisamide: a new drug for Parkinson’s disease. Drugs Today (Barc) 2010;46(4):251–8. Murata M, Hasegawa K, Kanazawa I. Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study. Neurology 2007;68(1): 45–50. Lyons KE, Pahwa R. Efficacy and tolerability of levetiracetam in Parkinson disease patients with levodopa-induced dyskinesia. Clin Neuropharmacol 2006;29(3):148–53. Ben-Ari Y. Cell death and synaptic reorganizations produced by seizures. Epilepsia 2001;42(Suppl 3):5–7. Scott MJ, Johnson GV. Microtubule/MAP-affinity regulating kinase (MARK) is activated by phenylarsine oxide in situ and phosphorylates tau within its microtubule-binding domain. J Neurochem 2000;74(4):1463–8. Jin X, Prince DA, Huguenard JR. Enhanced excitatory synaptic connectivity in layer V pyramidal neurons of chronically injured epileptogenic neocortex in rats. J Neurosci 2006;26(18):4891–900. Garcia ML, Cleveland DW. Going new places using an old MAP: tau, microtubules and human neurodegenerative disease. Curr Opin Cell Biol 2001;13:41–8. Jeon SH, Kim YS, Bae CD, Park JB. Activation of JNK and p38 in rat hippocampus after kainic acid induced seizure. Exp Mol Med 2000;32(4):227–30. Chuckowree JA, Vickers JC. Cytoskeletal and morphological alterations underlying axonal sprouting after localized transection of cortical neuron axons in vitro. J Neurosci 2003;23(9):3715–25. An SJ, See MO, Kim HS, Park SK, Hwang IK, Won MH, et al. Accumulation of microtubule-associated proteins in the hippocampal neurons of seizuresensitive gerbils. Mol Cells 2003;15(2):200–7. Yang L, Afroz S, Michelson HB, Goodman JH, Valsamis HA, Ling DS. Spontaneous epileptiform activity in rat neocortex after controlled cortical impact injury. J Neurotrauma 2010;27(8):1541–8. Isaeva E, Isaev D, Savrasova A, Khazipov R, Holmes GL. Recurrent neonatal seizures result in long-term increases in neuronal network excitability in the rat neocortex. Eur J Neurosci 2010;31(8):1446–55. Bonnet C, Boucher D, Lazereg S, Pedrotti B, Islam K, Denoulet P, et al. Differential binding regulation of microtubule-associated proteins MAP1A, MAP1B, and MAP2 by tubulin polyglutamylation. J Biol Chem 2001;276(16): 12839–48. Pei JJ, Gong CX, An WL, Winblad B, Cowburn RF, Grundke-Iqbal I, et al. Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer’s disease. Am J Pathol 2003;163:845–58. Ferrer I, Gomez-Isla T, Puig B, Freixes M, Ribe E, Dalfo E, et al. Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer’s disease and tauopathies. Curr Alzheimer Res 2005;2(1):3–18.
[44] Harris FM, Brecht WJ, Xu Q, Mahley RW, Huang Yd. Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase. J Biol Chem 2004;279(43): 44795–801. [45] Mukaetova-Ladinska EB, Garcia-Siera F, Hurt J, Gertz HJ, Xuereb JH, Hills R, et al. Staging of cytoskeletal and b-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer’s disease. Am J Pathol 2000;157:623–36. [46] Sontag E, Luangpirom A, Hladik C, Mudrak I, Ogris E, Speciale S, et al. Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology. J Neuropathol Exp Neurol 2004;63(4):287–301. [47] Pollard M, Khrestchatisky J, Moreau K, Ben-Ari Y, Represa A. Correlation between reactive sprouting and microtubule protein expression in epileptic hippocampus. Neuroscience 1994;61:273–87. [48] Proper EA, Oestreicher AB, Jansen GH, Veelen CW, van Rijen PC, Gispen WH, et al. Immunohistochemical characterization of mossy fibre sprouting in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 2000;123(1):19–30. [49] Xi ZQ, Xiao F, Yuan J, Wang XF, Wang L, Quan FY, et al. Gene expression analysis on anterior temporal neocortex of patients with intractable epilepsy. Synapse 2009;63(11):1017–28. [50] Pedrotti B, Francolini M, Cotelli F, Islam K. Modulation of microtubule shape in vitro by high molecular weight microtubule associated proteins MAP1A, MAP1B, and MAP2. FEBS Lett 1996;384(2):147–50. [51] Joly JC, Purich DL. Peptides corresponding to the second repeated sequence in MAP-2 inhibit binding of microtubule-associated proteins to microtubules. Biochemistry 1990;29:8916–20. [52] Al-Bassam J, Ozer RS, Safer D, Halpain S, Milligan RA. MAP2 and tau bind longitudinally along the outer ridges of microtubule protofilaments. J Cell Biol 2002;157(7):1187–96. [53] Palmio J, Suhonen J, Keränen T, Hulkkonen J, Peltola J, Pirttilä T. Cerebrospinal fluid tau as a marker of neuronal damage after epileptic seizure. Seizure 2009;18(7):474–7. [54] Sisodiya SM, Thom M, Lin WR, Bajaj NP, Cross JH, Harding BN. Abnormal expression of cdk5 in focal cortical dysplasia in humans. Neurosci Lett 2002;328(3):217–20. [55] Flugel D, Gorlach A, Michiels C, Kietzmann T. Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1{alpha} and mediates its destabilization in a VHL-independent manner. Mol Cell Biol 2007;27(9): 3253–65. [56] Engel T, Goni-Oliver P, Lucas JJ, Avila J, Hernandez F. Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but preformed neurofibrillary tangles do not revert. J Neurochem 2006;99(6): 1445–55. [57] Li T, Hawkes C, Qureshi HY, Kar S, Paudel HK. Cyclin-dependent protein kinase 5 primes microtubule-associated protein tau site-specifically for glycogen synthase kinase 3beta. Biochemistry 2006;45(10):3134–45. [58] Campos VE, Du M, Li Y. Increased seizure susceptibility and cortical malformation in beta-catenin mutant mice. Biochem Biophys Res Commun 2004;320(2):606–14. [59] Lohi H, Ianzano L, Zhao XC, Chan EM, Turnbull J, Scherer SW, et al. Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. Hum Mol Genet 2005;14(18):2727–36. [60] Bibb JA, Chen J, Taylor JR, Svenningsson P, Nishi A, Snyder Gretchen L, et al. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 2001;410:376–80. [61] Jingshan Chen, Yajun Zhang, Kelz Max B, Steffen Cathy, Ang Eugenius S, Zeng Ling, et al. Induction of cyclin-dependent kinase 5 in the hippocampus by chronic electroconvulsive seizures: role of FosB. J Neurosci 2000;20(24): 8965–71. [62] Sen A, Thom M, Martinian L, Jacobs T, Nikolic M, Sisodiya SM. Deregulation of cdk5 in hippocampal sclerosis. J Neuropathol Exp Neurol 2006;65(1):55–66.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Is intractable epilepsy a tauopathy? Zhi-Qin Xi a, Xue-Feng Wang a,⇑, Xiao-Fang Shu b, Guo-Jun Chen a, Fei Xiao a, Ji-Jun Sun a, Xi Zhu a a b
Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China Department of Gynaecology and Obstetrics, Central Hospital Mianyang City, Sichuan Province, China
a r t i c l e
i n f o
Article history: Received 22 July 2010 Accepted 3 March 2011
a b s t r a c t Tau exists in neuronal axons and glial cells of the central nervous system and contributes to the maintenance of the unique cell morphology. It functions in axon elongation, cell polarity formation and microtubule stabilization. Aggregates and hyper-phosphorylated tau proteins are classical components of neurofibrillary lesions in numerous neurodegenerative disorders, which are called ‘‘tauopathies’’. Recent studies have demonstrated that tau-associated genes and proteins and tau phosphorylation were abnormal in intractable epilepsy. Therefore, the discovery of the dysfunctional tau in intractable epilepsy opens a new window in the study of central tauopathy. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction Epilepsy, a disorder of recurrent seizures, is a common devastating neurological condition. More than 30 percent of patients with epilepsy have inadequate control of seizures even if treated with various antiepileptic drugs (AEDs) at maximum doses either alone or in combination. Such epileptic cases are referred to as intractable epilepsy (IE) [1,2]. A 2009 consensus proposal by the Task Force of the International League Against Epilepsy (ILAE) Commission defined drugresistant epilepsy as ‘‘a failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as a monotherapy or in combination) to achieve sustained seizure freedom’’ [2]. One half of the patients with medically IE are potential candidates for surgery. The temporal lobe epilepsy, frontal epilepsy, and progressive myoclonic epilepsies tend to be refractory to AED [1–3]. Temporal lobe epilepsy (TLE), especially mesial temporal sclerosis is an example of a surgically remediable syndrome [3]. One of the progressive myoclonic epilepsies, the focal cortical dysplasia (FCD), is the most common malformation of cortical development that undergoes surgical series [4]. Tauopathies result from abnormal tau phosphorylation, abnormal levels of tau, abnormal tau splicing, or mutations in the tau gene. Accumulations of hyper-phosphorylated tau (p-tau) proteins are present in neurons, astrocytes, and oligodendrocytes [5]. One of the properties of the tau protein is its ability to self-assemble into the filamentous structures that are the pathological hallmark of Alzheimer’s disease (AD) and other neurodegenerative disorders ⇑ Corresponding author. Address: Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, 1 You Yi Road, Chongqing 400016, China. Tel.: +86 23 89012878; fax: +86 23 68811487. E-mail address: [email protected] (X.-F. Wang). 0306-9877/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.03.003
[6–9]. Neurodegenerative conditions, particularly dementias, AD and Parkinson’ disease (PD), appear more frequently in people with epilepsy [10]. Previous literature has reported higher prevalence ratios (PR) of AD in younger adult epilepsy groups than in older ones (PR 40 vs. 7). Similarly, more epileptic attacks also occur in earlier stage of dementia and cerebral degeneration [11].
Hypothesis AD, PD, focal cortical dysplasia, and aging have manifestations that include epilepsy, tau dysfunctions and a responsiveness to anti-epileptic medications such as valproic acid and zonisamide [10–26]. On the other hand, abnormal tau presents in both human and animal models of epilepsy. We hypothesize that IE is also a tauopathy. This concept should be beneficial for increasing our understanding of epilepsy and other tauopathies and for exploring the essential pathophysiological changes accompanying the epileptic attacks.
Explanatory evidence Evidence suggests that tau is involved in the pathogenesis of IE. Interestingly, all tau-positive neurodegenerative disorders, including AD, PD, and Pick’s disease, are accompanied by recurrent secondary epileptic seizures. However, all tau-negative diseases, such as the frontal dementia of non-AD and non-pick type diseases, are not associated with secondary epileptic seizures [10–15]. For example, studies in humans have reported the prevalence of seizures in dementia and AD varies from 5% to 64% [11], indicating that seizures occur more frequently in these diseases than in the general population, and a younger age is a risk factor for seizures in AD. Patients
898
Z.-Q. Xi et al. / Medical Hypotheses 76 (2011) 897–900
with AD and other types of dementias have a greater risk (5–10 fold) of developing epilepsy compared to age-matched controls [10]. Seizure severity, in terms of symptomatology, frequency, and the responsiveness to antiepileptic drugs, are different in these degenerative disorders. In AD, generalized seizures are common, which usually originates from a partial seizure focus. In addition, complex partial status epilepticus and myoclonus have been reported as later manifestations [15,16,27]. Sixty-three of the 1738 AD patients listed in the Alzheimer Disease Patient Registry (ADPR) and Alzheimer Disease Research Center (ADRC) had epilepsy. Seventy-two percent of the 63 patients had complex partial seizure activity. Seventy-six percent of these patients had an excellent response to the AED therapy. Approximately one-third of these patients had dose-related side effects from an AED [13]. Other similarities between IE, AD, and PD are also found in terms of immunoreactivity for ubiquitin, amyloid b protein [6] b-amyloid precursor protein (APP) [7,28], apolipoprotein E [21–23], and a-synuclein [3]. These proteins are abnormally expressed in IE animal models and patients [3,20–23]. Immunoreactive APP and a-synuclein were elevated in surgically resected human temporal lobe tissue from patients with IE and in the animal pilocarpine model. Apolipoprotein E e4 is associated with several disease-related traits, including the increased risk of late posttraumatic seizures, the earlier onset of TLE, refractory complex partial seizures, reduced memory and verbal learning, and postictal confusion. The apolipoprotein E e3/e4 genotype was more frequently seen in the simple febrile convulsion group than in the complicated febrile convulsion group [21–23]. Most drugs, such as valproic acid, levetiracetam, and zonisamide, can be used to treat these diseases regardless of epilepsy. Valproic acid has been used for the past 10 years to control agitation in dementia [25,26]. Low dose levetiracetam treatment may reduce the observed hyperactivity and improve memory performance among individuals with mild cognitive impairment [26]. For AD, a multicenter, randomized, double-blinded, parallel-treatment, placebo-controlled study in Japan suggested that zonisamide (ZNS), as an add-on treatment, has efficacy in the treatment of motor symptoms in patients with PD. The duration of ‘‘off’’ time was significantly reduced in the ZNS groups vs. placebo, but dyskinesia was not increased in the ZNS groups [29]. Studies support the utility of zonisamide for other symptoms of PD [30]. Levetiracetam, for the treatment of PD patients with moderate-to-severe levodopainduced dyskinesia (LID) on stable dopaminergic therapy, showed mild anti-dyskinetic effects without a worsening of Parkinsonian symptoms or a compromise in levodopa efficacy [31].
Discussion Tau pathological effects in IE A current popularly accepted concept is that abnormal neuronal network formation is involved in intractable epileptogenesis. Morphological rearrangements in the mossy fiber synapses occur after seizures [32]. Research on granule cell hyperexcitability in patients and in numerous animal models of epilepsy has found a recurrent excitatory granule cell network formed by sprouting mossy fiber axons [33–36]. Aberrant axonal sprouting is modulated by a family of molecules called microtubule-associated proteins (MAPs) [37,38]. Studies on seizure semiology and seizure expression in the elderly have shown that complex partial seizures rarely originate in the temporal lobes. In most of these instances, neocortical seizures arrive from fronto-parietal regions and then the neuronal activity could spread into hippocampus [39]. Cellular loss in the hippocampal formation, changes in long-term potentiation maintenance, an alteration in kindling, an increased susceptibility to
status epilepticus, and neuronal damage from stroke are usually seen in the older epilepsy brain. All of these changes can lead to aberrant axonal sprouting [37–40]. Tau proteins belong to the family of MAPs. Six different isoforms of tau are present in the adult human brain [5,35,41]. Phosphorylated tau is the active form of tau. Enzymes capable of modulating tau phosphorylation include glycogen synthase kinase-3b (GSK-3b), cyclin-dependent kinase 5 (CDK5), the mitogen-activated protein kinase (MAPK) family members, and c-Jun NH2-terminal kinases (JNKs) [33,42–44]. The majority of sprouts are tipped by expanded growth cone-like structures that exhibit immunoreactivity for tau, although these cones are generally smaller than developmental growth cones [37]. Neuritic sprouting has been described in the CA1 region of the hippocampus during the early stages of AD and is associated predominantly with tau-immunoreactive neuritic plaques [43,45]. Furthermore, the extent of tau phosphorylation has been particularly associated with dendritic sprouting [45]. Morphologic rearrangements, which may occur after seizures, were studied in the mossy fiber synapses because they have unique morphologic and cytochemical features that allow their identification unambiguously by light and electron microscopy [32]. A majority of research on granule cell hyperexcitability in patients and in numerous animal models of epilepsy has found recurrent excitatory granule cell network formed by sprouted mossy fiber axons [33–36]. Tau exists in the neuronal axons and glial cells of the central nervous system and contributes to axonal elongation, the formation of neuronal polarity, the maintenance of the special morphology of neurons, and the normal assembly of microtubules [35,41]. Tau can be transported to the mossy fibers via axoplasmic flow and induces an abnormal growth of the mossy fibers to sprout and form new synaptic connections. These new connections transform local circuits in the hilus and in the inner molecular layer and establish abnormal excitatory networks between granule cells [46]. Moreover, proliferated nervous processes may establish abnormal synapses with adjacent neurons and contribute to the pathogenesis of IE through synaptic reorganization [41,46]. Animal models of epilepsy have shown that the hyperphosphorylation of MAPs temporally and spatially coincides with sprouting [40,47,48]. In the nucleus amygdala-kindled model of TLE, the distribution of increased MAPs was associated with the hyperplasia and hypertrophy of granular cell dendrites in the hippocampus dentate gyrus [48]. The results of our previous study showed that the up-regulated MAP1A, MAP2, tubulin, and kinesin in epilepsy might have enhanced the interaction of tau and the microtubule, which then led to the aberrant axonal sprouting [49]. The development and progression of IE is a complex multi-step process involving alterations in the expression and function of a variety of different genes. Using gene chips, we analyzed the gene expression profiles from brains of IE patients. We found tau-associated genes, including MAP1A (microtubule-associated protein 1A), MAP2, P38, CDK5, myoglobin 1E (MYO1E), laminin beta 1 (LAMB1), tubulin gamma 1 (TUBG1), casein kinase 2 (alpha 1 polypeptide) (CSNK2A1), glycogen synthase kinase 3b (GSK-3b), and cadherin 18 type 2, were up-regulated in IE, while tubulin delta 1 (TUBD1) and MAP1B were down-regulated [49]. The findings on MAP1A, MAP1B, MAP2, CDK5, MYO1E, and GSK-3b were consistent with those by previously published articles [20,49]. Some new abnormally-expressed genes, such as LAMB1, CSNK2A1, and TUBD1, have never been reported in IE. In animal epilepsy models, the hyperphosphorylation of MAPs temporally and spatially coincide with sprouting. In the nucleus amygdala-kindled model of TLE, the distribution of increased MAPs was associated with the hyperplasia and hypertrophy of granular cell dendrites in the hippocampus dentate gyrus [48]. MAP1A and MAP1B displayed different affinities to tubulin. The elevated MAPs increased their interaction with the microtubule. MAP2 competes
Z.-Q. Xi et al. / Medical Hypotheses 76 (2011) 897–900
with MAP1B for binding to tubulin [50,51]. The longitudinal binding of MAP2/tau proteins to protofilaments leads to microtubule stabilization by bridging the tubulin interfaces [41,52]. However, MAPs also regulate their binding affinity to microtubules by phosphorylation [42,44]. Abnormal tau levels were associated with either acute or remote symptomatic seizures. The presence of elevated cerebrospinal fluid (CSF) tau increases the probability of seizure attacks [53].
899
ing that IE is a true tauopathy. Overall, a better knowledge of how p-tau proteins are aggregated in neurological diseases is essential for the development of future differential diagnosis and therapeutic strategies. These therapies would hopefully find their application in not only IE but also other neurological disorders, in which a dysfunction of tau biology has been identified. Conflict of interest statement
Roles of tau kinases in epilepsy None declared. Tau is defined as a phosphoprotein. Kinases that are capable of phosphorylating tau at specific sites include glycogen synthase kinase 3b (GSK3b), cycline-dependent kinase 5 (CDK5). Tau can also be phosphorylated by protein kinase A (PKA), protein kinase C (PKC), Ca2+/calmodulin kinase II (CamKII) [42–44,54]. Although many kinases modify tau, GSK3b and CDK5 play important roles in the regulation of tau phosphorylation under physiological and pathological conditions. In the central nervous system, GSK-3b is developmentally regulated with peak levels of expression during axogenesis. GSK-3b is present in growing axons, but it is completely excluded from axons at the end of axogenesis [54]. In addition to glycogen synthase, the GSK-3b phosphorylates a number of substrates, including metabolic and signaling proteins, structural proteins, and transcription factors that regulate cell survival [55]. The inhibition of GSK-3b is associated with a reduction in axon growth and a dramatic increase in growth cone size. The over-expression of GSK-3b in the cortex and hippocampus leads to decreased levels of nuclear b-catenin, an increased phosphorylation of tau, neuronal cell death, and reactive astrocytosis [56,57]. Dysfunction of beta-catenin-mediated signaling pathways in mice leads to cortical malformation and an increased seizure susceptibility [58]. Lafora progressive myoclonus epilepsy is caused by defective laforin and is rapidly followed by IE. Laforin is a GSK3 Ser9 phosphatase. The dephosphorylation of GSK3 at Ser9 activates GSK3 resulting in the inhibition of glycogen synthase through phosphorylation at multiple sites [59]. CDK5 is a unique member of the CDK family that is activated by interactions with the regulatory proteins p35 and p39 that are expressed almost exclusively in postmitotic neurons. These proteins are essential for developing appropriate cortical laminar architecture and are implicated in synaptic transmission, synaptic plasticity, and neuronal signaling. Moreover, CDK5 likely plays a role in cellular motility and adhesion, drug addiction [60], and neurodegeneration. Chronic electroconvulsive seizures (ECS) in mice cause an increased phosphorylation of tau followed by an increase in CDK5 catalytic activity [61]. Abnormal CDK5 expression and the aggregation of this protein in focal cortical dysplasia are important causes of refractory epilepsy in humans, suggesting that CDK5 may be involved in this important epileptogenic pathology [54]. Recently, Sen et al. [62] also found hippocampal sclerosis (HS) in chronic medical IE in adults that showed an increased activity of CDK5 and its activator, the p35/p25 complex. Tauopathies are considered as a group of disorders that are the consequence of abnormal tau phosphorylation, abnormal levels of tau, abnormal tau splicing, or mutations in the tau gene. Lines of evidence have supported that tau phosphorylation and associated genes were increased in the IE patients and animal models. Axonal sprouting with hyperphosphorylated tau proteins might be a defining neuropathological characteristic of IE. Thus, we propose that IE is a new subclass of tauopathy. Conclusions The interaction of dysfunctional tau and its associated proteins might be related to the sprouting of neuronal axons in IE, suggest-
Acknowledgments Chongqing Medical Science and Technology Bureau of Research Projects (2009-2-356) and Chongqing Natural Science Fund (X1263-0200190012). References [1] Berg AT, Kelly MM. Defining intractability: comparisons among published definitions. Epilepsia 2006;47(2):431–6. [2] Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc task force of the ILAE commission on therapeutic strategies. Epilepsia 2010;51(6):1069–77. [3] Yang JW, Czech T, Felizardo M, Baumgartner C, Lubec G. Aberrant expression of cytoskeleton proteins in hippocampus from patients with mesial temporal lobe epilepsy. Amino Acids 2006;30(4):477–93. [4] Giulioni M, Martinoni M, Rubboli G, Marucci G, Marliani AF, Battaglia S, et al. Temporo-mesial extraventricular neurocytoma and cortical dysplasia in focal temporal lobe epilepsy. J Clin Neurosci 2011;18(1):147–8. [5] Binder LI, Frankfurter A, Rebhun LI. The distribution of tau in the mammalian central nervous system. J Cell Biol 1985;1:1371–8. [6] Lee VM-Y, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci 2001;24:1121–59. [7] Zhukareva V, Mann D, Pickering-Brown S, Uryu K, Shuck T, Shah K, et al. Sporadic Pick’s disease: a tauopathy characterized by a spectrum of pathological tau isoforms in gray and white matter. Ann Neurol 2002;51:730–9. [8] Lambourne SL, Sellers LA, Bush TG, Choudhury SK, Emson PC, Suh YH, et al. Increased tau phosphorylation on mitogen-activated protein kinase consensus sites and cognitive decline in transgenic models for Alzheimer’s disease and FTDP-17: evidence for distinct molecular processes underlying tau abnormalities. Mol Cell Biol 2005;25(1):278–93. [9] Veeranna Takahide K, Barry B, Odrljin T, Mohan P, Basavarajappa BS, Peterhoff C, et al. Calpain mediates calcium-induced activation of the Erk1, 2 MAPK pathway and cytoskeletal phosphorylation in neurons. Am J Pathol 2004;65:795–805. [10] Mendez M, Lim G. Seizures in elderly patients with dementia: epidemiology and management. Drugs Aging 2003;20(11):791–803. [11] Scarmeas N, Honig LS, Choi H, Cantero J, Brandt J, Blacker D, et al. Seizures in Alzheimer disease: who, when, and how common? Arch Neurol 2009;66(8):992–7. [12] Johannessen LC. Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs 2008;22(1):27–47. [13] Rao SC, Dove G, Cascino GD, Petersen RC. Recurrent seizures in patients with dementia: frequency, seizure-types and treatment outcome. Epilepsy Behav 2009;14(1):118–20. [14] Hommet C, Mondon K, Camus V, De Toffol B, Constans T. Epilepsy and dementia in the elderly. Dement Geriatr Cogn Disord 2008;25:293–300. [15] Mendez MF. Seizures in Alzheimer’s disease: clinicopathologic study. J Geriatr Psychiatry Neurol 1994;7(4):230–3. [16] Sirven JI. Acute and chronic seizures in patients older than 60 years. Mayo Clinic Proc 2001;76(2):175–83. [17] Pantazis G, Altenmueller1 DM, Feil B, Rona S, Kurth C, Rating D, et al. Clinical characteristics in focal cortical dysplasia: a retrospective evaluation in a series of 120 patients. Brain 2006;129(7):1907–16. [18] Leppika IE, Kellyb KM, deToledo-Morrellc L, Patrylod PR, DeLorenzoe1 RJ, Mathernf GW, et al. Basic research in epilepsy and aging. Basic research in epilepsy and aging. Epilepsy Res. 68 (Suppl. 1) 21–37. [19] Cloyda J, Hauserb W, Townec A, Ramsayd R, Mattsone R, Gilliamf F, et al. Epidemiological and medical aspects of epilepsy in the elderly. Epilepsy Res. 68 (Suppl. 1) 39–48. [20] Xiao F, Chen D, Lu Y, Xiao Z, Guan LF, Yuan J, et al. Proteomic analysis of cerebrospinal fluid from patients with idiopathic temporal lobe epilepsy. Brain Res 2009;1255:180–9. [21] Chapin JS, Busch RM, Janigro D, Dougherty M, Tilelli CQ, Lineweaver TT, et al. APOE epsilon4 is associated with postictal confusion in patients with
900
[22]
[23]
[24]
[25] [26] [27]
[28] [29] [30]
[31]
[32] [33]
[34]
[35]
[36] [37]
[38]
[39]
[40]
[41]
[42]
[43]
Z.-Q. Xi et al. / Medical Hypotheses 76 (2011) 897–900 medically refractory temporal lobe epilepsy. Epilepsy Res 2008;81(2-3): 220–4. Gambardella A, Aguglia U, Chifari R, Labate A, Manna I, Serra P, et al. ApoE epsilon4 allele and disease duration affect verbal learning in mild temporal lobe epilepsy. Epilepsia 2005;46(1):110–7. Busch RM, Lineweaver TT, Naugle RI, Kim KH, Gong Y, Tilelli CQ, et al. ApoEepsilon4 is associated with reduced memory in long-standing intractable temporal lobe epilepsy. Neurology 2007;68(6):409–14. Sporis D, Sertic J, Henigsberg N, Mahovic D, Bogdanovic N, Babic T. Association of refractory complex partial seizures with a polymorphism of ApoE genotype. J Cell Mol Med 2005;9(3):698–703. Zhang XZ, Li XJ, Zhang HY. Valproic acid as a promising agent to combat Alzheimer’s disease. Brain Res Bull 2010;15;81(1):3–6. Weiner MF, Womack KB, Martin-Cook K, Svetlik DA, Hynan LS. Levetiracetam for agitated Alzheimer’s disease patients. Int Psychogeriatr 2005;17(2):327–8. Gaitatzis A, Carroll K, Majeed A, Sander WJ. The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia 2004;45(12): 1613–22. Delacourte A, Buée LT. Au pathology: a marker of neurodegenerative disorders. Curr Opin Neurol 2000;13:371–6. Murata M. Zonisamide: a new drug for Parkinson’s disease. Drugs Today (Barc) 2010;46(4):251–8. Murata M, Hasegawa K, Kanazawa I. Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study. Neurology 2007;68(1): 45–50. Lyons KE, Pahwa R. Efficacy and tolerability of levetiracetam in Parkinson disease patients with levodopa-induced dyskinesia. Clin Neuropharmacol 2006;29(3):148–53. Ben-Ari Y. Cell death and synaptic reorganizations produced by seizures. Epilepsia 2001;42(Suppl 3):5–7. Scott MJ, Johnson GV. Microtubule/MAP-affinity regulating kinase (MARK) is activated by phenylarsine oxide in situ and phosphorylates tau within its microtubule-binding domain. J Neurochem 2000;74(4):1463–8. Jin X, Prince DA, Huguenard JR. Enhanced excitatory synaptic connectivity in layer V pyramidal neurons of chronically injured epileptogenic neocortex in rats. J Neurosci 2006;26(18):4891–900. Garcia ML, Cleveland DW. Going new places using an old MAP: tau, microtubules and human neurodegenerative disease. Curr Opin Cell Biol 2001;13:41–8. Jeon SH, Kim YS, Bae CD, Park JB. Activation of JNK and p38 in rat hippocampus after kainic acid induced seizure. Exp Mol Med 2000;32(4):227–30. Chuckowree JA, Vickers JC. Cytoskeletal and morphological alterations underlying axonal sprouting after localized transection of cortical neuron axons in vitro. J Neurosci 2003;23(9):3715–25. An SJ, See MO, Kim HS, Park SK, Hwang IK, Won MH, et al. Accumulation of microtubule-associated proteins in the hippocampal neurons of seizuresensitive gerbils. Mol Cells 2003;15(2):200–7. Yang L, Afroz S, Michelson HB, Goodman JH, Valsamis HA, Ling DS. Spontaneous epileptiform activity in rat neocortex after controlled cortical impact injury. J Neurotrauma 2010;27(8):1541–8. Isaeva E, Isaev D, Savrasova A, Khazipov R, Holmes GL. Recurrent neonatal seizures result in long-term increases in neuronal network excitability in the rat neocortex. Eur J Neurosci 2010;31(8):1446–55. Bonnet C, Boucher D, Lazereg S, Pedrotti B, Islam K, Denoulet P, et al. Differential binding regulation of microtubule-associated proteins MAP1A, MAP1B, and MAP2 by tubulin polyglutamylation. J Biol Chem 2001;276(16): 12839–48. Pei JJ, Gong CX, An WL, Winblad B, Cowburn RF, Grundke-Iqbal I, et al. Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer’s disease. Am J Pathol 2003;163:845–58. Ferrer I, Gomez-Isla T, Puig B, Freixes M, Ribe E, Dalfo E, et al. Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer’s disease and tauopathies. Curr Alzheimer Res 2005;2(1):3–18.
[44] Harris FM, Brecht WJ, Xu Q, Mahley RW, Huang Yd. Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase. J Biol Chem 2004;279(43): 44795–801. [45] Mukaetova-Ladinska EB, Garcia-Siera F, Hurt J, Gertz HJ, Xuereb JH, Hills R, et al. Staging of cytoskeletal and b-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer’s disease. Am J Pathol 2000;157:623–36. [46] Sontag E, Luangpirom A, Hladik C, Mudrak I, Ogris E, Speciale S, et al. Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology. J Neuropathol Exp Neurol 2004;63(4):287–301. [47] Pollard M, Khrestchatisky J, Moreau K, Ben-Ari Y, Represa A. Correlation between reactive sprouting and microtubule protein expression in epileptic hippocampus. Neuroscience 1994;61:273–87. [48] Proper EA, Oestreicher AB, Jansen GH, Veelen CW, van Rijen PC, Gispen WH, et al. Immunohistochemical characterization of mossy fibre sprouting in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 2000;123(1):19–30. [49] Xi ZQ, Xiao F, Yuan J, Wang XF, Wang L, Quan FY, et al. Gene expression analysis on anterior temporal neocortex of patients with intractable epilepsy. Synapse 2009;63(11):1017–28. [50] Pedrotti B, Francolini M, Cotelli F, Islam K. Modulation of microtubule shape in vitro by high molecular weight microtubule associated proteins MAP1A, MAP1B, and MAP2. FEBS Lett 1996;384(2):147–50. [51] Joly JC, Purich DL. Peptides corresponding to the second repeated sequence in MAP-2 inhibit binding of microtubule-associated proteins to microtubules. Biochemistry 1990;29:8916–20. [52] Al-Bassam J, Ozer RS, Safer D, Halpain S, Milligan RA. MAP2 and tau bind longitudinally along the outer ridges of microtubule protofilaments. J Cell Biol 2002;157(7):1187–96. [53] Palmio J, Suhonen J, Keränen T, Hulkkonen J, Peltola J, Pirttilä T. Cerebrospinal fluid tau as a marker of neuronal damage after epileptic seizure. Seizure 2009;18(7):474–7. [54] Sisodiya SM, Thom M, Lin WR, Bajaj NP, Cross JH, Harding BN. Abnormal expression of cdk5 in focal cortical dysplasia in humans. Neurosci Lett 2002;328(3):217–20. [55] Flugel D, Gorlach A, Michiels C, Kietzmann T. Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1{alpha} and mediates its destabilization in a VHL-independent manner. Mol Cell Biol 2007;27(9): 3253–65. [56] Engel T, Goni-Oliver P, Lucas JJ, Avila J, Hernandez F. Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but preformed neurofibrillary tangles do not revert. J Neurochem 2006;99(6): 1445–55. [57] Li T, Hawkes C, Qureshi HY, Kar S, Paudel HK. Cyclin-dependent protein kinase 5 primes microtubule-associated protein tau site-specifically for glycogen synthase kinase 3beta. Biochemistry 2006;45(10):3134–45. [58] Campos VE, Du M, Li Y. Increased seizure susceptibility and cortical malformation in beta-catenin mutant mice. Biochem Biophys Res Commun 2004;320(2):606–14. [59] Lohi H, Ianzano L, Zhao XC, Chan EM, Turnbull J, Scherer SW, et al. Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. Hum Mol Genet 2005;14(18):2727–36. [60] Bibb JA, Chen J, Taylor JR, Svenningsson P, Nishi A, Snyder Gretchen L, et al. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 2001;410:376–80. [61] Jingshan Chen, Yajun Zhang, Kelz Max B, Steffen Cathy, Ang Eugenius S, Zeng Ling, et al. Induction of cyclin-dependent kinase 5 in the hippocampus by chronic electroconvulsive seizures: role of FosB. J Neurosci 2000;20(24): 8965–71. [62] Sen A, Thom M, Martinian L, Jacobs T, Nikolic M, Sisodiya SM. Deregulation of cdk5 in hippocampal sclerosis. J Neuropathol Exp Neurol 2006;65(1):55–66.