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New insights into progressive supranuclear palsy
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New insights into progressive supranuclear palsy David S. Albers and Sarah J. Augood Increased oxidative damage and mitochondrial dysfunction have been suggested to play crucial roles in the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease. In this review, we will focus on progressive supranuclear palsy (PSP), a rare parkinsonian disorder with tau pathology. Particular emphasis is placed on the genetic and biochemical data that has emerged, offering new perspectives into the pathogenesis of this devastating disease, especially the contributory roles of oxidative damage and mitochondrial dysfunction.
David S. Albers Dept of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA. e-mail: daa2010@ mail.med.cornell.edu Sarah J. Augood Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. e-mail: augood@ helix.mgh.harvard.edu
Progressive supranuclear palsy (PSP) is a hypokinetic movement disorder, characterized by parkinsonism (rigidity, slowed movements, tremor) and abnormal eye movements. The prevalence of PSP is ~5–6 per 100 000 people1, approximately one tenth that of Parkinson’s disease (PD). The average age of onset of PSP is 50–70 years2 and it neither favors race nor gender, although there is a tendency for males to be affected more frequently than females3. The progression of PSP is rapid and the median survival after the onset of symptoms is 5–10 years. The etiology of this debilitating disorder remains unknown, and at present, there is no effective treatment as PSP patients, unlike those with PD, are generally unresponsive to L-dopa. PSP was first described in detail as a separate clinical entity in 1964 (Ref. 4). In this seminal paper, Steele, Richardson and Olszewski documented the clinical symptoms of nine male patients and superimposed their observations on the underlying pathology at autopsy of four of these cases. They noted that, unlike many other neurodegenerative disorders, the clinical spectrum of PSP is relatively homogeneous, involving a ‘peculiar combination of oculomotor, dystonic, pseudobulbar, and mental signs’4. Prominent postural instability and the presence of falls are often presenting symptoms but supranuclear gaze abnormalities, particularly in the vertical plane, spastic or ataxic dysarthria (slurred speech) and dysphagia (swallowing problems) are also characteristic. PSP patients exhibit marked behavioral and cognitive symptoms attributable to frontal lobe dysfunction, such as apathy, depression and bradyphrenia (slowed mental activity)5 that are associated with marked frontal lobe glucose hypometabolism (see Ref. 6 for review). PSP has a distinctive topographical and molecular pathology characterized by marked neuronal degeneration and gliosis in multiple subcortical and brain stem nuclei. Most devastation
is localized to several basal ganglia (Fig. 1a) and brainstem structures including the subthalamic nucleus (STN), the globus pallidus (GP), and the midbrain and pontine reticular formations. The superior colliculus, locus coeruleus, ventral arm of the dentate nucleus and vestibular nuclei are also affected4,7–14. The histopathological signature of PSP is fibrillary gliosis, demyelination, intracytoplasmic vacuoles and the presence of straight15 neurofibrillary tangles (NFTs) that displace the Nissl substance and the nucleus peripherally to resemble ‘inclusion bodies’14. Within the caudateputamen, there is a selective loss of large cholinergic neurons16 and a prevalence of tufted astrocytes9. These abnormal astrocytic profiles are also found in numerous cortical regions, including layer V of the frontal cortex, and within the thalamus – brain regions relatively spared of cell loss. Consistent with a degeneration of neurons in the ventral arm of the dentate nucleus, cerebellar torpedoes have been described within Purkinje cell processes suggesting that they might occur as a consequence of synaptic disconnection17. Genetics of PSP
PSP is considered to be a sporadic disorder despite reports showing familial clustering18 and a recent description of a silent mutation in exon 10 of the tau gene in an Australian family member with PSP-like pathology19. Indeed, the tau locus on chromosome 17q21 has been identified as a potential risk factor for developing the disease20–22. Conrad and colleagues initially described an association between sporadic PSP and a polymorphic dinucleotide marker found between exons 9 and 10 (A0 haplotype)20. Subsequent association studies identified a significant overrepresentation of a more common H1 haplotype that spans the entire tau gene21. Recently, an extended 5′-tau haplotype, HapA, corresponding to four contiguous single nucleotide polymorphisms in exons 1, 4A and 8 has been identified in 98% of PSP cases and appears to be the most sensitive and specific marker for sporadic PSP (Ref. 23). However, this haplotype is also found in 33% of controls, thus the occurrence of PSP must require additional exogenous24 or genetic factors. To date, no linkage has been found between PSP and α-synuclein25, a candidate gene for familial early-onset PD (Ref. 26), or the ApoE4 allele27, a risk factor for late-onset, familial AD (Ref. 28).
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(a)
(b) CN
Put GPi
STN
SNc Fig. 1. Pathology of progressive supranuclear palsy within the basal ganglia. (a) Macroscopic view of a hemi-coronal slice through the basal ganglia of a typical progressive supranuclear palsy (PSP) brain. Note the shrunken substantia nigra pars compacta (SNc), subthalamic nucleus (STN) and pallidal complex, particularly the internal segment of the globus pallidus (GPi), consistent with a marked loss of neurons. By contrast, the caudate nucleus (CN) and putamen (Put) are relatively well preserved. (b) Example of tau-immunopositive tufted astrocytes (arrows) within the putamen of a PSP brain.
PSP is a tauopathy
Tau is a phosphoprotein that belongs to a family of microtubule-associated proteins. In the adult human brain there are six tau isoforms that are generated by alternative splicing of exons 2, 3 and 10 (Ref. 29) resulting in isoforms containing either three or four microtubule binding domains30. In the PSP brain, there is a selective enrichment of tau isoforms containing four microtubule binding domains (4-repeat tau)31, particularly the 64 and 69 kDa isoforms32 that result from the splicing-in of exon 10 [E10+]. These two isoforms are hyperphosphorylated, as revealed by two-dimensional gel electrophoresis 1
Oxidative damage r = –0.77
0.75 MDA (µmol/ml)
and phospho-specific tau antibodies32,33. Tau pathology – consisting of neuropil threads, neuritic plaques, tufted astrocytes (Fig. 1b), glial inclusions, microglia and globose tangles – is observed in the postmortem PSP brain. Specifically, hyperphosphorylated tau-positive tufted astrocytes within the putamen, and oligodendroglia within the white matter, are characteristic features of PSP (Refs 9,34). That mutations within the tau gene can be pathogenic is evidenced by frontotemporal dementia parkinsonism linked to chromosome 17 (FTDP-17), a neurological disorder characterized by marked cognitive impairment and hypokinesia. FTDP-17 is caused by autosomal dominant in-frame mutations within the tau gene (for review, see Ref. 35), which alter the stoichiometry of the isoforms generated (i.e. the 3-repeat:4-repeat ratio). These genetic mutations also impact on the biochemical properties of these isoforms, resulting in insoluble filamentous aggregates of hyperphosphorylated 4-repeat tau in neurons and glia36,37. For example, in FTDP-17 pedigrees bearing the V337M mutation, tau deposits are detected exclusively in neurons, whereas in pedigrees bearing the most common P301L mutation, deposits are detected in neurons, astrocytes and oligodendrocytes (for review, see Ref. 38). Interestingly, transgenic mice overexpressing human 4-repeat tau have been generated and recapitulate some, but not all, of the prototypical characteristics of these tauopathies39. Recently, mice transgenic for the human P301L tau mutation have been generated and were found to develop an age- and gene-dose dependent phenotype with glial pathology and hyperphosphorylated 4-repeat tau NFTs, reminiscent of PSP (Ref. 40).
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0 0
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4
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Fig. 2. Negative correlation between tissue malondialdehyde (MDA) levels and cell loss in the subthalamic nucleus (STN) in progressive supranuclear palsy (PSP). Tissue MDA content in the STN from eight pathologically confirmed progressive supranuclear palsy (PSP) cases was measured using a sensitive and specific HPLC-based assay44. The extent of pathology (i.e. cell loss) was rated (J.P. Vonsattel) with 1 = minimal; 2 = mild; 3 = moderate; 4 = severe.
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One hypothesis to explain the hyperphosphorylation of tau is that free radical-induced oxidative stress, particularly membrane lipid peroxidation, renders tau resistant to dephosphorylation41. Free radicals such as hydroxyl (OH•), superoxide (O2−•), nitric oxide (NO•) and peroxynitrite (ONOO−•) extract electrons from neighboring molecules to complete their orbital, thus leading to the oxidation of cellular components. Oxidative damage to proteins, membrane lipids, DNA and RNA is well-documented in several neurodegenerative diseases (for reviews, see Refs 42,43). Recently, PSP has been added to the list, because increased tissue malondialdehyde (MDA) and 4-hydroxynonenal, markers of lipid peroxidation, have been found in the subthalamic nucleus (Fig. 2), superior frontal cortex and midbrain44–46. In particular, a negative correlation exists between tissue MDA levels and neuronal pathology (Fig. 2), suggesting oxidative damage occurs in neurons. In addition, an increase in inducible nitric oxide synthase (iNOS) protein has been reported within tufted astrocytes, suggesting
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Mg2+ Glu Glycine
NMDA receptor
[Ca2+]i
MMP activity
NOS
SOD
mtDNA oxidation Protein oxidation Lipid peroxidation
ONOO–
NO• + O2– O2–
Hyperphosphorylated tau P tau P P Transglutaminase
[Ca2+]i
H2O2
Catalase
H2O
Paired helical filaments (PHFs)
Fe2+
ATP
OH• ETC
Protein oxidation nDNA/RNA oxidation Lipid peroxidation
Mitochondria
NFTs/tau aggregates Nucleus
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Fig. 3. The potential deleterious effects of compromised energy metabolism. Decreased energy levels (↓ATP) results in partial membrane depolarization relieving the Mg2+ block of the NMDA receptor. NMDA receptor-mediated Ca2+ influx ([Ca2+]i) can result in increased sequestering of Ca2+ into mitochondria leading to the formation of superoxide (O2•) radicals, activation of nitric oxide synthase (NOS) and matrix metalloproteases (MMPs). The reaction of O2• and NO generates peroxynitrite (ONOO–) – a key mediator of oxidative damage. Ca2+-dependent activation of transglutaminase can lead to the crosslinking of hyperphosphorylated tau into pathologic aggregates.
that they are at least one possible source of NO radicals in the PSP brain47. A compensatory cellular response to increased free radical production is to upregulate antioxidant defense systems, such as superoxide dismutase (SOD), catalase and reduced glutathione (GSH). In PD, compromised antioxidant systems have been suggested to underlie the cellular vulnerability to oxidative stress48. Consistent with this idea, antioxidant systems have been examined in PSP (Refs 49–54). Increased SOD activity, SOD protein levels and total glutathione content have been reported in multiple cortical and subcortical PSP brain regions49,54. Further, the increases in tissue glutathione content and SOD1 (Cu/ZnSOD) activity parallel the extent of reactive gliosis, suggesting that these changes are attributable, in part, to a glial reaction. However, in a pre-clinical case of PSP (J.P. Vonsattel, pers. commun.), increased SOD activities have also been observed, in the absence of reactive gliosis, suggesting a compensatory increase in SOD activity within neurons as well54. In typical PSP, SOD immunostudies have localized the SOD changes to a proliferation of SOD1 and SOD2 (MnSOD) immunopositive cells within both white matter and basal ganglia structures54; many of these cells http://tins.trends.com
resemble microglia. Furthermore, both tau-positive tufted astrocytes and globose tangles are immunopositive for SOD2 (Refs 47,54). Together, these findings are consistent with activated glia being a primary source of SOD activity within the typical PSP brain. Thus, in contrast to PD, these findings suggest that there is no overt underlying deficit in antioxidant defense mechanisms in the PSP brain. Another consequence of increased free radical production, in particular NO•, is the induction of matrix metalloproteinases (MMPs)55, which are a family of Zn2+-containing, Ca2+-requiring endopeptidases characterized by their ability to digest otherwise stable components of the extracellular matrix (for review, see Ref. 56). Recently, we have found increased expression and activity of MMP-2 and -9, a subset of MMPs known as gelatinases, in PSP brain tissue and cerebrospinal fluid (CSF) samples57. Similar increases have been reported in postmortem AD brain tissue56 where a role for oxidative stress has been firmly established58. Transition metal ions and bioenergetic defects
If alterations in brain antioxidants and MMPs in the PSP brain are secondary to oxidative damage, then there are several possible primary sources of free radicals. One source is the accumulation of prooxidant transition metal ions, including iron (Fe2+), copper (Cu2+) and zinc (Zn2+), which catalyze the formation of the highly reactive hydroxyl (OH•) radical via Fenton reactions. Increased Fe2+ concentrations have been reported within the PSP basal ganglia59 and hyperphosphorylated tau
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Another source of free radicals is mitochondria. Recent findings have identified defects in mitochondrial metabolism in PSP brain and skeletal muscle45,63,64. Specifically, the activity of the αketoglutarate dehydrogenase complex, the ratelimiting step in the tricarboxylic acid cycle, is significantly reduced in the postmortem superior frontal cortex45 and deficits in ATP metabolism are observed in skeletal muscle and brain using phosphorous magnetic resonance spectroscopy (P-MRS)63. This P-MRS study is the first direct demonstration of an abnormality in mitochondrial metabolism in PSP patients. Notably, the brain P-MRS spectra observed in these PSP patients are similar to those observed in patients with mitochondrial cytopathies65.
Mitochondrial dysfunction
Oxidative stress - Oxidative damage to DNA, RNA, protein and lipids - Increased transition metal ions - Increased iNOS levels
- Increased free radical production
NFTs
- MMP activation - Hyperphosphorylation of tau
- Decreased complex I activity, aconitase, KGDHC activities - Decreased ATP levels 2+ - Impaired Ca buffering 2+ - Increased [Ca ]i
- Depolymerization of microtubules - Increased transglutaminase activity
Tau - Overexpression of 4-repeat tau
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Mitochondrial impairment Fig. 4. The possible interactions between oxidative stress, mitochondrial dysfunction and tau in the formation of neurofibrillary tangles (NFTs) in progressive supranuclear palsy (PSP). There are significant interactions between oxidative stress and mitochondrial energy metabolism. Mitochondria are the most contributory source of intracellular free radicals. Thus, any impairment of mitochondrial function increases the levels of free radicals generated resulting in additional oxidative damage to mitochondrial proteins, lipids and DNA further causing mitochondrial dysfunction. The age-related incidence and progressive nature of PSP might be caused by interactions between oxidative damage and defects in energy metabolism. Further, these processes, in combination with genetic or environmental factors, might lead to the depolymerization of microtubules and hyperphosphorylation of overexpressed 4-repeat tau resulting ultimately in the formation of NFTs and cell loss.
deposits have been shown to be immunoreactive for ferritin60 suggesting that increased transition metal ions might promote, albeit indirectly, the formation of tau aggregates. Interestingly, these tau deposits are immunopositive for COOH-terminal α-synuclein61 but not nitrosylated α-synuclein62. Table 1. Changes in mitochondrial and oxidative parameters in PSPa PSP
PD
AD
Aging
Mitochondrial dysfunction Complex I Complex II–III Complex IV KGDHC Aconitase
↓ ? − ↓ ↓
↓ − − ↓ −
− − ↓ ↓ ?
↓ − ↓ ? ?
Oxidative damage MDA 4-HNE Protein carbonyls Nitrotyrosine OH8dG Transition metal ions
↑ ↑ ? ? ? ↑Fe2+↓Cu2+
↑ ↑ ↑ ? ↑ ↑Zn2+↑Fe2+↓Cu2+
↑ ↑ ↑ ↑ ↑ ↓Zn2+↑Fe2+↓Cu2+
↑ ↑ ↑ ? ↑ ?
Antioxidants Catalase SOD Glutathione
? ↑ ↑
↓ ↑ ↓
↑ ↑ −
− ↓ −
Genetic risk factors
Tau
KGDHC α-synuclein Parkin UCHL-1
NOS3 Presenilin ApoE4 APP
a↓
= decrease; ↑ = increase; dash (−) = no change; ? = remains to be determined; adapted from Ref. 58. Abbreviations: AD, Alzheimer’s disease; APP, amyloid precursor protein; KGDHC, alphaketoglutarate dehydrogenase complex; MDA, malondialdehyde; NOS, nitric oxide synthase; PD, Parkinson’s disease; PSP, progressive supranuclear palsy; SOD, superoxide dismutase.
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Mitochondrial DNA (mtDNA) is susceptible to free radical attack as a result of a lack of protective histones, limited DNA repair capabilities and proximity to the electron transport chain. Mitochondrial dysfunction leads to decreased ATP levels, impaired cellular Ca2+ buffering, activation of nitric oxide synthase (NOS) and the generation of NO radicals (Fig. 3). A novel technique to establish whether mitochondrial defects play a primary or secondary role in a disease process is to generate cytoplasmic hybrids, known as cybrids66. Cybrids are generated by introducing mitochondria from a patient’s platelets into a human neuroblastoma or osteocarcinoma cell line that lacks mtDNA and is therefore devoid of oxidative phosphorylation. The resultant cybrids can be used to determine whether defects in oxidative phosphorylation are attributable to mutations encoded by the donor patient’s mitochondrial genome. PSP cybrids have recently been generated and specific defects in complex I activity have been identified; complex IV activity was unchanged67. We have observed impaired oxygen consumption and significant decreases in ATP levels in these PSP cybrids68. Furthermore, the activity of aconitase, an iron–sulfur protein that catalyzes the first two steps of the citric acid cycle and is sensitive to oxidative damage69–72, is also significantly decreased68. These data are consistent with the bioenergetic defects reported in vivo63 and, together with the complex I defect67, further establishes mitochondrial dysfunction in the pathogenesis of PSP. Whether these functional abnormalities observed in the PSP cybrids result from inherited or acquired mtDNA mutations remain to be determined. Other mechanisms
In PD and other neurodegenerative disorders, the concept of slow or weak excitotoxicity has been proposed as a potential mechanism of cell death73. Slow excitotoxicity might occur as a consequence of decreased cellular ATP levels leading to partial
Review
Acknowledgements We thank S. Lorenzl, I. Cantuti-Castelvetri, C.E. Keller-McGandy, J. Chirichigno, D.G. Standaert and M. Flint Beal for their contributions to this work. J-P. Vonsattel is thanked for providing the pathological images in Fig. 1. Our research was supported, in part, by the Society for Progressive Supranuclear Palsy.
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neuronal depolarization and activation of NMDA receptors by physiological levels of glutamate. The resultant increases in intracellular Ca2+ can initiate several toxic processes (Fig. 3), including generation of NO and depolymerization of microtubules74 resulting in increased levels of soluble tau protein, which, coupled with altered transglutaminase activity in the PSP brain75, might underlie the formation of NFTs (Fig. 4). Interestingly, these NFTs are immunoreactive for frameshift mutant ubiquitin-B (Ref. 76). Thus, it is tempting to speculate that when intracellular Ca2+ levels are increased, transglutaminase, a Ca2+-dependent enzyme, becomes abnormally activated and crosslinks hyperphosphorylated tau and/or stabilizes tau aggregates preventing their degradation.
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Future perspectives and concluding remarks
Significant advances have been made in elucidating the etiology of neurodegeneration in PSP. Growing, albeit circumstantial, evidence suggests a complex interplay between genetic predisposition, oxidative damage and mitochondrial dysfunction. These mechanisms probably interact with processes involved in normal aging (Table 1). Thus, defects in energy metabolism might be clinically dormant until age-related decreases in oxidative metabolism pass a critical threshold. Further studies are required to investigate the link between metabolic and oxidative events and the formation of hyperphosphorylated tau aggregates in PSP. The recent generation of mice transgenic for human 4-repeat tau40 should significantly aid this endeavor.
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52 Smith, M.A. et al. (1994) Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer’s disease. Am. J. Pathol. 145, 42–47 53 Loeffler, D.A. et al. (1996) Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders. Brain Res. 738, 265–274 54 Cantuti-Castelvetri, I. et al. (2000) Antioxidant enzymes in progressive supranuclear palsy brain. Soc. Neurosci. Abstr. 26, 1798 55 Murrell, G.A. et al. (1995) Nitric oxide activates metalloprotease enzymes in articular cartilage. Biochem. Biophys. Res. Commun. 206, 15–21 56 Yong, V.W. et al. (1998) Matrix metalloproteinases and diseases of the CNS. Trends Neurosci. 21, 75–80 57 Albers, D.S. et al. (2000) Increased expression of gelatinases in Parkinson’s disease and progressive supranuclear palsy. Soc. Neurosci. Abstr. 26, 1027 58 Albers, D.S. and Beal, M.F. (2000) Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease. J. Neural Transm. (Suppl.) 59, 133–154 59 Dexter, D.T. et al. (1992) Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. Ann. Neurol. 32, S94–S100 60 Perez, M. et al. (1998) Ferritin is associated with the aberrant tau filaments present in progressive supranuclear palsy. Am. J. Pathol. 152, 1531–1539 61 Takeda, A. et al. (2000) C-terminal alphasynuclein immunoreactivity in structures other than Lewy bodies in neurodegenerative disorders. Acta Neuropathol. (Berlin) 99, 296–304 62 Giasson, B.I. et al. (2000) Oxidative damage linked to neurodegeneration by selective alphasynuclein nitration in synucleinopathy lesions. Science 290, 985–989 63 Martinelli, P. et al. (2000) Deficit of brain and skeletal muscle bioenergetics in progressive supranuclear palsy shown in vivo by phosphorus magnetic resonance spectroscopy. Mov. Disord. 15, 889–893
64 DiMonte, D. et al. (1994) Muscle mitochondrial ATP production in progressive supranuclear palsy. J. Neurochem. 62, 1631–1634 65 Barbiroli, B. et al. (1999) Low brain intracellular free magnesium in mitochondrial cytopathies. J. Cereb. Blood Flow Metab. 19, 528–532 66 King, M.P. and Attardi, G. (1989) Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246, 500–503 67 Swerdlow, R.H. et al. (2000) Mitochondrial dysfunction in cybrid lines expressing mitochondrial genes from patients with progressive supranuclear palsy. J. Neurochem. 75, 1681–1684 68 Albers, D.S. et al. (2001) Further evidence for mitochondrial dysfunction in progressive supranuclear palsy. Exp. Neurol. 168, 196–198 69 Patel, M. et al. (1996) Requirement for superoxide in excitotoxic cell death. Neuron 16, 345–355 70 Grune, T. et al. (1998) Peroxynitrite increases the degradation of aconitase and other cellular proteins by proteasome. J. Biol. Chem. 273, 10857–10862 71 Brown, G.C. (1999) Nitric oxide and mitochondrial respiration. Biochim. Biophys. Acta Mol. Cell Res. 1411, 351–369 72 Cooper, C.E. (1999) Nitric oxide and iron proteins. Biochim. Biophys. Acta Mol. Cell Res. 1411, 290–309 73 Albin, R.L. and Greenamyre, J.T. (1992) Alternative excitotoxic hypotheses. Neurology 42, 733–738 74 O’Brien, E.T. et al. (1997) How calcium causes microtubule depolymerization. Cell Motil. Cytoskeleton 36, 125–135 75 Zemaitaitis, M.O. et al. (2000) Transglutaminaseinduced cross-linking of tau proteins in progressive supranuclear palsy. J. Neuropathol. Exp. Neurol. 59, 983–989 76 Fergusson, J. et al. (2000) Neurofibrillary tangles in progressive supranuclear palsy brains exhibit immunoreactivity to frameshift mutant ubiquitin–B protein. Neurosci. Lett. 279, 69–72
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New insights into progressive supranuclear palsy David S. Albers and Sarah J. Augood Increased oxidative damage and mitochondrial dysfunction have been suggested to play crucial roles in the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease. In this review, we will focus on progressive supranuclear palsy (PSP), a rare parkinsonian disorder with tau pathology. Particular emphasis is placed on the genetic and biochemical data that has emerged, offering new perspectives into the pathogenesis of this devastating disease, especially the contributory roles of oxidative damage and mitochondrial dysfunction.
David S. Albers Dept of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA. e-mail: daa2010@ mail.med.cornell.edu Sarah J. Augood Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. e-mail: augood@ helix.mgh.harvard.edu
Progressive supranuclear palsy (PSP) is a hypokinetic movement disorder, characterized by parkinsonism (rigidity, slowed movements, tremor) and abnormal eye movements. The prevalence of PSP is ~5–6 per 100 000 people1, approximately one tenth that of Parkinson’s disease (PD). The average age of onset of PSP is 50–70 years2 and it neither favors race nor gender, although there is a tendency for males to be affected more frequently than females3. The progression of PSP is rapid and the median survival after the onset of symptoms is 5–10 years. The etiology of this debilitating disorder remains unknown, and at present, there is no effective treatment as PSP patients, unlike those with PD, are generally unresponsive to L-dopa. PSP was first described in detail as a separate clinical entity in 1964 (Ref. 4). In this seminal paper, Steele, Richardson and Olszewski documented the clinical symptoms of nine male patients and superimposed their observations on the underlying pathology at autopsy of four of these cases. They noted that, unlike many other neurodegenerative disorders, the clinical spectrum of PSP is relatively homogeneous, involving a ‘peculiar combination of oculomotor, dystonic, pseudobulbar, and mental signs’4. Prominent postural instability and the presence of falls are often presenting symptoms but supranuclear gaze abnormalities, particularly in the vertical plane, spastic or ataxic dysarthria (slurred speech) and dysphagia (swallowing problems) are also characteristic. PSP patients exhibit marked behavioral and cognitive symptoms attributable to frontal lobe dysfunction, such as apathy, depression and bradyphrenia (slowed mental activity)5 that are associated with marked frontal lobe glucose hypometabolism (see Ref. 6 for review). PSP has a distinctive topographical and molecular pathology characterized by marked neuronal degeneration and gliosis in multiple subcortical and brain stem nuclei. Most devastation
is localized to several basal ganglia (Fig. 1a) and brainstem structures including the subthalamic nucleus (STN), the globus pallidus (GP), and the midbrain and pontine reticular formations. The superior colliculus, locus coeruleus, ventral arm of the dentate nucleus and vestibular nuclei are also affected4,7–14. The histopathological signature of PSP is fibrillary gliosis, demyelination, intracytoplasmic vacuoles and the presence of straight15 neurofibrillary tangles (NFTs) that displace the Nissl substance and the nucleus peripherally to resemble ‘inclusion bodies’14. Within the caudateputamen, there is a selective loss of large cholinergic neurons16 and a prevalence of tufted astrocytes9. These abnormal astrocytic profiles are also found in numerous cortical regions, including layer V of the frontal cortex, and within the thalamus – brain regions relatively spared of cell loss. Consistent with a degeneration of neurons in the ventral arm of the dentate nucleus, cerebellar torpedoes have been described within Purkinje cell processes suggesting that they might occur as a consequence of synaptic disconnection17. Genetics of PSP
PSP is considered to be a sporadic disorder despite reports showing familial clustering18 and a recent description of a silent mutation in exon 10 of the tau gene in an Australian family member with PSP-like pathology19. Indeed, the tau locus on chromosome 17q21 has been identified as a potential risk factor for developing the disease20–22. Conrad and colleagues initially described an association between sporadic PSP and a polymorphic dinucleotide marker found between exons 9 and 10 (A0 haplotype)20. Subsequent association studies identified a significant overrepresentation of a more common H1 haplotype that spans the entire tau gene21. Recently, an extended 5′-tau haplotype, HapA, corresponding to four contiguous single nucleotide polymorphisms in exons 1, 4A and 8 has been identified in 98% of PSP cases and appears to be the most sensitive and specific marker for sporadic PSP (Ref. 23). However, this haplotype is also found in 33% of controls, thus the occurrence of PSP must require additional exogenous24 or genetic factors. To date, no linkage has been found between PSP and α-synuclein25, a candidate gene for familial early-onset PD (Ref. 26), or the ApoE4 allele27, a risk factor for late-onset, familial AD (Ref. 28).
http://tins.trends.com 0166-2236/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0166-2236(00)01794-X
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(a)
(b) CN
Put GPi
STN
SNc Fig. 1. Pathology of progressive supranuclear palsy within the basal ganglia. (a) Macroscopic view of a hemi-coronal slice through the basal ganglia of a typical progressive supranuclear palsy (PSP) brain. Note the shrunken substantia nigra pars compacta (SNc), subthalamic nucleus (STN) and pallidal complex, particularly the internal segment of the globus pallidus (GPi), consistent with a marked loss of neurons. By contrast, the caudate nucleus (CN) and putamen (Put) are relatively well preserved. (b) Example of tau-immunopositive tufted astrocytes (arrows) within the putamen of a PSP brain.
PSP is a tauopathy
Tau is a phosphoprotein that belongs to a family of microtubule-associated proteins. In the adult human brain there are six tau isoforms that are generated by alternative splicing of exons 2, 3 and 10 (Ref. 29) resulting in isoforms containing either three or four microtubule binding domains30. In the PSP brain, there is a selective enrichment of tau isoforms containing four microtubule binding domains (4-repeat tau)31, particularly the 64 and 69 kDa isoforms32 that result from the splicing-in of exon 10 [E10+]. These two isoforms are hyperphosphorylated, as revealed by two-dimensional gel electrophoresis 1
Oxidative damage r = –0.77
0.75 MDA (µmol/ml)
and phospho-specific tau antibodies32,33. Tau pathology – consisting of neuropil threads, neuritic plaques, tufted astrocytes (Fig. 1b), glial inclusions, microglia and globose tangles – is observed in the postmortem PSP brain. Specifically, hyperphosphorylated tau-positive tufted astrocytes within the putamen, and oligodendroglia within the white matter, are characteristic features of PSP (Refs 9,34). That mutations within the tau gene can be pathogenic is evidenced by frontotemporal dementia parkinsonism linked to chromosome 17 (FTDP-17), a neurological disorder characterized by marked cognitive impairment and hypokinesia. FTDP-17 is caused by autosomal dominant in-frame mutations within the tau gene (for review, see Ref. 35), which alter the stoichiometry of the isoforms generated (i.e. the 3-repeat:4-repeat ratio). These genetic mutations also impact on the biochemical properties of these isoforms, resulting in insoluble filamentous aggregates of hyperphosphorylated 4-repeat tau in neurons and glia36,37. For example, in FTDP-17 pedigrees bearing the V337M mutation, tau deposits are detected exclusively in neurons, whereas in pedigrees bearing the most common P301L mutation, deposits are detected in neurons, astrocytes and oligodendrocytes (for review, see Ref. 38). Interestingly, transgenic mice overexpressing human 4-repeat tau have been generated and recapitulate some, but not all, of the prototypical characteristics of these tauopathies39. Recently, mice transgenic for the human P301L tau mutation have been generated and were found to develop an age- and gene-dose dependent phenotype with glial pathology and hyperphosphorylated 4-repeat tau NFTs, reminiscent of PSP (Ref. 40).
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0 0
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Fig. 2. Negative correlation between tissue malondialdehyde (MDA) levels and cell loss in the subthalamic nucleus (STN) in progressive supranuclear palsy (PSP). Tissue MDA content in the STN from eight pathologically confirmed progressive supranuclear palsy (PSP) cases was measured using a sensitive and specific HPLC-based assay44. The extent of pathology (i.e. cell loss) was rated (J.P. Vonsattel) with 1 = minimal; 2 = mild; 3 = moderate; 4 = severe.
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One hypothesis to explain the hyperphosphorylation of tau is that free radical-induced oxidative stress, particularly membrane lipid peroxidation, renders tau resistant to dephosphorylation41. Free radicals such as hydroxyl (OH•), superoxide (O2−•), nitric oxide (NO•) and peroxynitrite (ONOO−•) extract electrons from neighboring molecules to complete their orbital, thus leading to the oxidation of cellular components. Oxidative damage to proteins, membrane lipids, DNA and RNA is well-documented in several neurodegenerative diseases (for reviews, see Refs 42,43). Recently, PSP has been added to the list, because increased tissue malondialdehyde (MDA) and 4-hydroxynonenal, markers of lipid peroxidation, have been found in the subthalamic nucleus (Fig. 2), superior frontal cortex and midbrain44–46. In particular, a negative correlation exists between tissue MDA levels and neuronal pathology (Fig. 2), suggesting oxidative damage occurs in neurons. In addition, an increase in inducible nitric oxide synthase (iNOS) protein has been reported within tufted astrocytes, suggesting
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Mg2+ Glu Glycine
NMDA receptor
[Ca2+]i
MMP activity
NOS
SOD
mtDNA oxidation Protein oxidation Lipid peroxidation
ONOO–
NO• + O2– O2–
Hyperphosphorylated tau P tau P P Transglutaminase
[Ca2+]i
H2O2
Catalase
H2O
Paired helical filaments (PHFs)
Fe2+
ATP
OH• ETC
Protein oxidation nDNA/RNA oxidation Lipid peroxidation
Mitochondria
NFTs/tau aggregates Nucleus
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Fig. 3. The potential deleterious effects of compromised energy metabolism. Decreased energy levels (↓ATP) results in partial membrane depolarization relieving the Mg2+ block of the NMDA receptor. NMDA receptor-mediated Ca2+ influx ([Ca2+]i) can result in increased sequestering of Ca2+ into mitochondria leading to the formation of superoxide (O2•) radicals, activation of nitric oxide synthase (NOS) and matrix metalloproteases (MMPs). The reaction of O2• and NO generates peroxynitrite (ONOO–) – a key mediator of oxidative damage. Ca2+-dependent activation of transglutaminase can lead to the crosslinking of hyperphosphorylated tau into pathologic aggregates.
that they are at least one possible source of NO radicals in the PSP brain47. A compensatory cellular response to increased free radical production is to upregulate antioxidant defense systems, such as superoxide dismutase (SOD), catalase and reduced glutathione (GSH). In PD, compromised antioxidant systems have been suggested to underlie the cellular vulnerability to oxidative stress48. Consistent with this idea, antioxidant systems have been examined in PSP (Refs 49–54). Increased SOD activity, SOD protein levels and total glutathione content have been reported in multiple cortical and subcortical PSP brain regions49,54. Further, the increases in tissue glutathione content and SOD1 (Cu/ZnSOD) activity parallel the extent of reactive gliosis, suggesting that these changes are attributable, in part, to a glial reaction. However, in a pre-clinical case of PSP (J.P. Vonsattel, pers. commun.), increased SOD activities have also been observed, in the absence of reactive gliosis, suggesting a compensatory increase in SOD activity within neurons as well54. In typical PSP, SOD immunostudies have localized the SOD changes to a proliferation of SOD1 and SOD2 (MnSOD) immunopositive cells within both white matter and basal ganglia structures54; many of these cells http://tins.trends.com
resemble microglia. Furthermore, both tau-positive tufted astrocytes and globose tangles are immunopositive for SOD2 (Refs 47,54). Together, these findings are consistent with activated glia being a primary source of SOD activity within the typical PSP brain. Thus, in contrast to PD, these findings suggest that there is no overt underlying deficit in antioxidant defense mechanisms in the PSP brain. Another consequence of increased free radical production, in particular NO•, is the induction of matrix metalloproteinases (MMPs)55, which are a family of Zn2+-containing, Ca2+-requiring endopeptidases characterized by their ability to digest otherwise stable components of the extracellular matrix (for review, see Ref. 56). Recently, we have found increased expression and activity of MMP-2 and -9, a subset of MMPs known as gelatinases, in PSP brain tissue and cerebrospinal fluid (CSF) samples57. Similar increases have been reported in postmortem AD brain tissue56 where a role for oxidative stress has been firmly established58. Transition metal ions and bioenergetic defects
If alterations in brain antioxidants and MMPs in the PSP brain are secondary to oxidative damage, then there are several possible primary sources of free radicals. One source is the accumulation of prooxidant transition metal ions, including iron (Fe2+), copper (Cu2+) and zinc (Zn2+), which catalyze the formation of the highly reactive hydroxyl (OH•) radical via Fenton reactions. Increased Fe2+ concentrations have been reported within the PSP basal ganglia59 and hyperphosphorylated tau
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Another source of free radicals is mitochondria. Recent findings have identified defects in mitochondrial metabolism in PSP brain and skeletal muscle45,63,64. Specifically, the activity of the αketoglutarate dehydrogenase complex, the ratelimiting step in the tricarboxylic acid cycle, is significantly reduced in the postmortem superior frontal cortex45 and deficits in ATP metabolism are observed in skeletal muscle and brain using phosphorous magnetic resonance spectroscopy (P-MRS)63. This P-MRS study is the first direct demonstration of an abnormality in mitochondrial metabolism in PSP patients. Notably, the brain P-MRS spectra observed in these PSP patients are similar to those observed in patients with mitochondrial cytopathies65.
Mitochondrial dysfunction
Oxidative stress - Oxidative damage to DNA, RNA, protein and lipids - Increased transition metal ions - Increased iNOS levels
- Increased free radical production
NFTs
- MMP activation - Hyperphosphorylation of tau
- Decreased complex I activity, aconitase, KGDHC activities - Decreased ATP levels 2+ - Impaired Ca buffering 2+ - Increased [Ca ]i
- Depolymerization of microtubules - Increased transglutaminase activity
Tau - Overexpression of 4-repeat tau
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Mitochondrial impairment Fig. 4. The possible interactions between oxidative stress, mitochondrial dysfunction and tau in the formation of neurofibrillary tangles (NFTs) in progressive supranuclear palsy (PSP). There are significant interactions between oxidative stress and mitochondrial energy metabolism. Mitochondria are the most contributory source of intracellular free radicals. Thus, any impairment of mitochondrial function increases the levels of free radicals generated resulting in additional oxidative damage to mitochondrial proteins, lipids and DNA further causing mitochondrial dysfunction. The age-related incidence and progressive nature of PSP might be caused by interactions between oxidative damage and defects in energy metabolism. Further, these processes, in combination with genetic or environmental factors, might lead to the depolymerization of microtubules and hyperphosphorylation of overexpressed 4-repeat tau resulting ultimately in the formation of NFTs and cell loss.
deposits have been shown to be immunoreactive for ferritin60 suggesting that increased transition metal ions might promote, albeit indirectly, the formation of tau aggregates. Interestingly, these tau deposits are immunopositive for COOH-terminal α-synuclein61 but not nitrosylated α-synuclein62. Table 1. Changes in mitochondrial and oxidative parameters in PSPa PSP
PD
AD
Aging
Mitochondrial dysfunction Complex I Complex II–III Complex IV KGDHC Aconitase
↓ ? − ↓ ↓
↓ − − ↓ −
− − ↓ ↓ ?
↓ − ↓ ? ?
Oxidative damage MDA 4-HNE Protein carbonyls Nitrotyrosine OH8dG Transition metal ions
↑ ↑ ? ? ? ↑Fe2+↓Cu2+
↑ ↑ ↑ ? ↑ ↑Zn2+↑Fe2+↓Cu2+
↑ ↑ ↑ ↑ ↑ ↓Zn2+↑Fe2+↓Cu2+
↑ ↑ ↑ ? ↑ ?
Antioxidants Catalase SOD Glutathione
? ↑ ↑
↓ ↑ ↓
↑ ↑ −
− ↓ −
Genetic risk factors
Tau
KGDHC α-synuclein Parkin UCHL-1
NOS3 Presenilin ApoE4 APP
a↓
= decrease; ↑ = increase; dash (−) = no change; ? = remains to be determined; adapted from Ref. 58. Abbreviations: AD, Alzheimer’s disease; APP, amyloid precursor protein; KGDHC, alphaketoglutarate dehydrogenase complex; MDA, malondialdehyde; NOS, nitric oxide synthase; PD, Parkinson’s disease; PSP, progressive supranuclear palsy; SOD, superoxide dismutase.
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Mitochondrial DNA (mtDNA) is susceptible to free radical attack as a result of a lack of protective histones, limited DNA repair capabilities and proximity to the electron transport chain. Mitochondrial dysfunction leads to decreased ATP levels, impaired cellular Ca2+ buffering, activation of nitric oxide synthase (NOS) and the generation of NO radicals (Fig. 3). A novel technique to establish whether mitochondrial defects play a primary or secondary role in a disease process is to generate cytoplasmic hybrids, known as cybrids66. Cybrids are generated by introducing mitochondria from a patient’s platelets into a human neuroblastoma or osteocarcinoma cell line that lacks mtDNA and is therefore devoid of oxidative phosphorylation. The resultant cybrids can be used to determine whether defects in oxidative phosphorylation are attributable to mutations encoded by the donor patient’s mitochondrial genome. PSP cybrids have recently been generated and specific defects in complex I activity have been identified; complex IV activity was unchanged67. We have observed impaired oxygen consumption and significant decreases in ATP levels in these PSP cybrids68. Furthermore, the activity of aconitase, an iron–sulfur protein that catalyzes the first two steps of the citric acid cycle and is sensitive to oxidative damage69–72, is also significantly decreased68. These data are consistent with the bioenergetic defects reported in vivo63 and, together with the complex I defect67, further establishes mitochondrial dysfunction in the pathogenesis of PSP. Whether these functional abnormalities observed in the PSP cybrids result from inherited or acquired mtDNA mutations remain to be determined. Other mechanisms
In PD and other neurodegenerative disorders, the concept of slow or weak excitotoxicity has been proposed as a potential mechanism of cell death73. Slow excitotoxicity might occur as a consequence of decreased cellular ATP levels leading to partial
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Acknowledgements We thank S. Lorenzl, I. Cantuti-Castelvetri, C.E. Keller-McGandy, J. Chirichigno, D.G. Standaert and M. Flint Beal for their contributions to this work. J-P. Vonsattel is thanked for providing the pathological images in Fig. 1. Our research was supported, in part, by the Society for Progressive Supranuclear Palsy.
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neuronal depolarization and activation of NMDA receptors by physiological levels of glutamate. The resultant increases in intracellular Ca2+ can initiate several toxic processes (Fig. 3), including generation of NO and depolymerization of microtubules74 resulting in increased levels of soluble tau protein, which, coupled with altered transglutaminase activity in the PSP brain75, might underlie the formation of NFTs (Fig. 4). Interestingly, these NFTs are immunoreactive for frameshift mutant ubiquitin-B (Ref. 76). Thus, it is tempting to speculate that when intracellular Ca2+ levels are increased, transglutaminase, a Ca2+-dependent enzyme, becomes abnormally activated and crosslinks hyperphosphorylated tau and/or stabilizes tau aggregates preventing their degradation.
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Future perspectives and concluding remarks
Significant advances have been made in elucidating the etiology of neurodegeneration in PSP. Growing, albeit circumstantial, evidence suggests a complex interplay between genetic predisposition, oxidative damage and mitochondrial dysfunction. These mechanisms probably interact with processes involved in normal aging (Table 1). Thus, defects in energy metabolism might be clinically dormant until age-related decreases in oxidative metabolism pass a critical threshold. Further studies are required to investigate the link between metabolic and oxidative events and the formation of hyperphosphorylated tau aggregates in PSP. The recent generation of mice transgenic for human 4-repeat tau40 should significantly aid this endeavor.
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