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Axonal transport failure in neurodegenerative disorders: the case of Huntington’s disease
Pathologie Biologie 53 (2005) 189–192 http://france.elsevier.com/direct/PATBIO/
Editorial
Axonal transport failure in neurodegenerative disorders: the case of Huntington’s disease Altération du transport axonal et maladies neurodégénératives : la maladie de Huntington Keywords: Intracellular trafficking; Neurodegeneration; Huntington’s disease; Polyglutamine Mots clés : Traffic intracellulaire ; Neurodégénérescence ; Maladie de Huntington ; Polyglutamine
1. Introduction Neurodegenerative disorders are a group of inherited or acquired diseases of the nervous system. They are characterized by the death of specific populations of neurons, leading to precise clinical features. For most of these diseases, it is not yet understood how specific neurons degenerate and die. Huntington’s disease (HD) is a dominantly inherited neurodegenerative disease caused by abnormal polyglutamine (polyQ) expansion in a target protein. HD is characterized by uncontrolled movements (chorea), personality changes and dementia. Patients typically die 10–20 years after the appearance of the first clinical symptoms [1]. It is caused by the specific dysfunction and death of neurons from the striatum (a region of the brain important for monitoring movements). The mutated protein is huntingtin: a large ubiquitous protein, the function of which is not yet fully understood. However, there is some evidence that huntingtin is an anti-apoptotic protein [2]. Indeed, it is necessary for development, as knockout mice die shortly after gastrulation [3] and conditional knock-out mice, in which huntingtin is turned off during adulthood, develop neurodegenerative disease [4]. Moreover, overexpression of huntingtin protects striatal cells from a variety of apoptotic stimuli [5]. Huntingtin becomes toxic when it contains an abnormal polyQ expansion. PolyQ-huntingtin induces the formation of neuritic and intranuclear inclusions, neuronal dysfunction and finally neuronal death. The precise mechanisms underlying these phenomena are not well understood and it is not known how increased neuronal death in the brain relates to huntingtin function and dysfunction. Recent evidences suggest that huntingtin is involved in intracellular transport. Indeed, cytoplasmic huntingtin colocalizes with microtubules [6] and interacts with ß-tubulin [7]. 0369-8114/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.patbio.2004.12.008
It also interacts with huntingtin-associated protein 1 (HAP1), which is implicated in trafficking, huntingtin-interacting proteins 1 and 14 (HIP1 and HIP14), which are involved in endocytosis and trafficking, and PACSIN1 (protein kinase C and casein kinase substrate in neurons1), which is involved in endocytosis [8–12]. Here, we will review recent studies demonstrating that huntingtin plays a role in intracellular transport and that the alteration of this process results in HD. We will also discuss the general importance of transport in neurodegenerative disorders.
2. Intracellular transport and neurons Neurons are highly polarized cells composed of a cell body and an extensive network of cell processes: dendrites and a single axon. The axonal extension can reach up to one meter in length. Most protein synthesis is restricted to the cell body. Therefore, active transport is required to supply the axon with the newly synthesized material. Conversely, external signals have to be transmitted to the cell body, where the signaling cascade is activated. Here also, active transport of receptor/ligand complexes is required for a quick and appropriate response [13,14]. Due to the length of their processes, transport efficiency is of particular importance in neurons. To allow efficient communication between cell bodies and axon termini, molecular motor proteins continuously shuttle vesicles and organelles along the microtubules and actin filaments that make up the cellular cytoskeleton. This transport process mostly involves microtubules, which are polarized structures with “plus” (cell extremity) and “minus” (cell body) ends. Molecular motors are considered to be unidirectional:
190
Editorial / Pathologie Biologie 53 (2005) 189–192
dynein complexes are connected to retrograde transport (from plus to minus end), whereas kinesins are connected to anterograde transport (from cell body to plasma membrane) [15–18]. These two classes of motor complexes are required for efficient transport in neurons. Disruption of these complexes has dramatic consequences on neurons and leads to severe diseases.
3. Huntingtin and transport In Drosophila, a reduction in huntingtin protein expression causes axonal transport defects in larval nerves and neurodegeneration in adult eyes [19]. This strongly supports the hypothesis that huntingtin plays a crucial role in intracellular trafficking. Indeed, Gauthier et al. [20] demonstrate that huntingtin plays a role in the intracellular transport of brainderived neurotrophic factor (BDNF). Why study BDNF? BDNF is an important factor in HD. It is produced in the cortex and transported to the striatum, the major site of degeneration in HD, where it supports neuronal differentiation and survival. It inhibits polyQ-huntingtininduced neuronal death and its level is abnormally low in HD patients. This low level is partly due to a decreased BDNF gene transcription in the disease situation [21]. Gauthier et al. show that BDNF transport from the cortex to the striatum is also altered in disease and demonstrate that huntingtin plays a stimulatory role in axonal transport. Normal full-length huntingtin stimulates BDNF transport. The mutant form has lost this ability, leading to reduced BDNF support and thus to increasing susceptibility of striatal neurons to death. This phenotype is mediated by HAP1, which interacts with huntingtin and with the p150Glued subunit of dynactin. Huntingtin normally interacts with p150Glued via HAP1 and stimulates BDNF transport. In contrast, when huntingtin contains an abnormal polyQ expansion, it interacts more strongly with HAP1 and p150Glued, leading to the detachment of the molecular motors from the microtubules and thus to less efficient transport of BDNF vesicles.
and terminals [25]. What are the consequences of these aggregates on axonal transport? N-terminal huntingtin polypeptide fragments containing the polyQ expansion cause axonal transport defects [19,26–28], which subsequently induce neuronal death. Alteration in transport could be due to a physical blockage of vesicles but could also involve the titration by mutant huntingtin aggregates of motor proteins (particularly p150Glued and kinesin heavy chain) from other cargoes and pathways. In conclusion, in early stages of the disease, the role of huntingtin in transport is lost following the disruption of the huntingtin (soluble form)/HAP1 interaction. In later stages, polyQ-huntingtin forms neuritic aggregates that contribute to a trafficking defect by a gain of function mechanism.
5. Disruption of cellular transport: a common phenomenon in neurodegenerative disorders Transport defects have also been described in other polyQ neurodegenerative disorders. The polyQ-containing androgen receptor (AR), responsible for spinobulbar muscular atrophy (SBMA), inhibits fast axonal transport [26,29]. Non polyQ neurodegenerative diseases have also been linked to transport failure. In Alzheimer’s disease (AD), the amyloid precursor protein (APP), responsible for familial forms of AD, disrupts axonal transport [30]. Similarly, overexpression of tau, a neuronal microtubule-associated protein that accumulates in AD, blocks organelle trafficking [31]. Several different neurodegenerative disorders are caused by mutation within motor proteins. For instance, Charcot–Marie–Tooth disease type 2 is caused by a loss-of-function mutation in the kinesin KIF1B [32], and hereditary spastic paraplegia type 10 is caused by a missense mutation in KIF5A [33]. Finally, a mutation in p150Glued subunit of dynactin has been identified in a family with an autosomal dominant form of lower motor neurons disease [34]. In agreement, inhibition of dynein-mediated axonal transport causes neurodegeneration in mice models [35,36].
4. PolyQ aggregates and transport
6. Concluding remarks
The study by Gauthier et al. demonstrates that at least part of the anti-apoptotic properties of huntingtin are linked to its stimulatory effect on the transport of BDNF, a key neurotrophic factor. They also show that loss of the BDNF transport function by huntingtin may be an early step in HD. Another critical step in HD pathogenesis is the cleavage of polyQ-huntingtin into N-terminal fragments containing the polyQ expansion. These fragments translocate into the nucleus and induce the formation of aggregates [22]. In the nucleus, polyQ-huntingtin fragments cause neuronal death by a gain of function leading to the dysregulation of transcriptional activity [23,24]. In addition, N-terminal huntingtin fragments and their aggregates accumulate in axonal processes
Slowing of transport might be a general phenomenon in neurodegenerative diseases. It can be either causative or contributory depending on the disease. Neurons are highly susceptible to dysregulation of transport. Indeed, as transport in neurons occurs over very long distances, a decrease in intracellular trafficking has dramatic consequences on their viability. The development of accurate models of intracellular transport in neurons should therefore help to understand the molecular mechanisms underlying these diseases. Axonal transport is a promising target for designing and testing treatments to slow or to block neurodegeneration. In the case of HD, compounds that enhance transport or rescue huntingtin dysfunction might be of therapeutic interest as hun-
Editorial / Pathologie Biologie 53 (2005) 189–192
191
tingtin directly controls transport of the pro-survival factor BDNF. This is of utmost importance, as no treatment currently exists for this devastating disorder.
[12] Modregger J, DiProspero NA, Charles V, Tagle DA, Plomann M. PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington’s disease brains. Hum Mol Genet 2002;11:2547–58.
Acknowledgements
[13] Kuruvilla R, Zweifel LS, Glebova NO, Lonze BE, Valdez G, Ye H, et al. A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling. Cell 2004;118:243–55.
We thank members of the Saudou/Humbert’s laboratory for helpful comments. Our work is supported by grants from CNRS, Association pour la Recherche sur le Cancer (ARC no. 4807), Fondation pour la Recherche Médicale and Fondation BNP Paribas, Association Francaise contre les Myopathies (AFM), Provital/P. Chevalier, Hereditary Disease Foundation Cure HD Initiative and HighQ Foundation to F.S. and S.H. B.C.C. was supported by Hereditary Disease Foundation Cure HD Initiative and is currently funded by Association pour la Recherche sur le Cancer. F.S. is recipient of an EMBOYoung Investigator award and an Inserm/AP-HP investigator. S.H. is an Inserm investigator.
[14] Heerssen HM, Pazyra MF, Segal RA. Dynein motors transport activated Trks to promote survival of target-dependent neurons. Nat Neurosci 2004;7:596–604.
References
[20] Gauthier LR, Charrin BC, Borrell-Pagès M, Dompierre JP, Rangonne H, Cordelières FP, et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular trannsport along microtubules. Cell 2004;118:127–38.
[1]
Martin JB, Gusella JF. Huntington’s disease. Pathogenesis and management. N Engl J Med 1986;315:1267–76.
[2]
Rangone H, Humbert S, Saudou F. Huntington’s disease: how does huntingtin, an anti-apoptotic protein, become toxic? Pathol Biol (Paris) 2004;52:338–42.
[3]
Zeitlin S, Liu JP, Chapman DL, Papaioannou VE, Efstratiadis A. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat Genet 1995;11: 155–63.
[4]
[5]
[6]
[7]
Dragatsis I, Levine MS, Zeitlin S. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet 2000;26:300–6. Rigamonti D, Sipione S, Goffredo D, Zuccato C, Fossale E, Cattaneo E. Huntingtin’s neuroprotective activity occurs via inhibition of procaspase-9 processing. J Biol Chem 2001;276:14545–8. Gutekunst CA, Levey AI, Heilman CJ, Whaley WL, Yi H, Nash NR, et al. Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. Proc Natl Acad Sci USA 1995;92:8710–4. Hoffner G, Kahlem P, Djian P. Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: relevance to Huntington’s disease. J Cell Sci 2002; 115:941–8.
[8]
Li XJ, Li SH, Sharp AH, Nucifora Jr. FC, Schilling G, Lanahan A, et al. A huntingtin-associated protein enriched in brain with implications for pathology. Nature 1995;378:398–402.
[9]
Kalchman MA, Koide HB, McCutcheon K, Graham RK, Nichol K, Nishiyama K, et al. HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain. Nat Genet 1997;16:44–53.
[10] Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Walter S, Tait D, et al. HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system. Hum Mol Genet 1997;6:487–95. [11] Singaraja RR, Hadano S, Metzler M, Givan S, Wellington CL, Warby S, et al. HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis. Hum Mol Genet 2002;11:2815–28.
[15] Vallee RB, Hook P. Molecular motors: a magnificent machine. Nature 2003;421:701–2. [16] Vale RD. The molecular toolbox for intracellular transport. Cell 2003; 112:467–80. [17] Hirokawa N, Takemura R. Kinesin superfamily proteins and their various functions and dynamics. Exp Cell Res 2004;301:50–9. [18] Hirokawa N. Kinesin and dynein superfamily proteins and the mechanism of organelle transport. Science 1998;279:519–26. [19] Gunawardena S, Her LH, Brusch RG, Laymon RA, Niesman IR, Gordesky-Gold B, et al. Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 2003;40:25–40.
[21] Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 2001;293:493–8. [22] DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997;277:1990–3. [23] Saudou F, Finkbeiner S, Devys D, Greenberg ME. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998;95:55–66. [24] Ross CA. Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington’s disease and related disorders. Neuron 2002;35:819–22. [25] Li H, Li SH, Johnston H, Shelbourne PF, Li XJ. Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nat Genet 2000;25:385–9. [26] Szebenyi G, Morfini GA, Babcock A, Gould M, Selkoe K, Stenoien DL, et al. Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 2003;40:41–52. [27] Trushina E, Dyer RB, Badger JD, Ure D, Eide L, Tran DD, et al. Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol Cell Biol 2004;24:8195–209. [28] Lee WC, Yoshihara M, Littleton JT. Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington’s disease. Proc Natl Acad Sci USA 2004;101:3224–9. [29] Piccioni F, Pinton P, Simeoni S, Pozzi P, Fascio U, Vismara G, et al. Androgen receptor with elongated polyglutamine tract forms aggregates that alter axonal trafficking and mitochondrial distribution in motor neuronal processes. FASEB J 2002;16:1418–20. [30] Gunawardena S, Goldstein LSB. Disruption of axonal transport and neuronal viability by amiloid precursor mutations in Drosophila. Neuron 2001;32:389–401. [31] Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxydative stress. J Cell Biol 2002;156:1051–63.
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[32] Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, et al. Charcot–Marie–Tooth disease type 2A caused by mutation in a microtubule motor KIF1B beta. Cell 2001;105:587–97. [33] Reid E, Kloos M, Ashley-Koch A, Hughes L, Bevan S, Svenson IK, et al. A kinesin heavy chain (KIF5A) mutation in hereditary spasic paraplegia (SPG10). Am J Hum Genet 2002;71:1189–94. [34] Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, et al. Mutant dynactin in motor neuron disease. Nat Genet 2003;33: 455–6. [35] Hafezparast M, Klocke R, Ruhrberg C, Marquardt A, AhmadAnnuar A, Bowen S, et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 2003;300: 808–12. [36] LaMonte BH, Wallace KE, Holloway BA, Shelly SS, Ascano J, Tokito M, et al. Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron 2002;34:715–27.
Bénédicte C. Charrin Frédéric Saudou * Sandrine Humbert * UMR 146 CNRS/Institut Curie, Bldg. 110, Centre Universitaire, 91405 Orsay cedex, France E-mail address: [email protected] (F. Saudou). E-mail address: [email protected] (S. Humbert). Received 29 November 2004; accepted 9 December 2004 Available online 22 January 2005 * Corresponding authors.
Editorial
Axonal transport failure in neurodegenerative disorders: the case of Huntington’s disease Altération du transport axonal et maladies neurodégénératives : la maladie de Huntington Keywords: Intracellular trafficking; Neurodegeneration; Huntington’s disease; Polyglutamine Mots clés : Traffic intracellulaire ; Neurodégénérescence ; Maladie de Huntington ; Polyglutamine
1. Introduction Neurodegenerative disorders are a group of inherited or acquired diseases of the nervous system. They are characterized by the death of specific populations of neurons, leading to precise clinical features. For most of these diseases, it is not yet understood how specific neurons degenerate and die. Huntington’s disease (HD) is a dominantly inherited neurodegenerative disease caused by abnormal polyglutamine (polyQ) expansion in a target protein. HD is characterized by uncontrolled movements (chorea), personality changes and dementia. Patients typically die 10–20 years after the appearance of the first clinical symptoms [1]. It is caused by the specific dysfunction and death of neurons from the striatum (a region of the brain important for monitoring movements). The mutated protein is huntingtin: a large ubiquitous protein, the function of which is not yet fully understood. However, there is some evidence that huntingtin is an anti-apoptotic protein [2]. Indeed, it is necessary for development, as knockout mice die shortly after gastrulation [3] and conditional knock-out mice, in which huntingtin is turned off during adulthood, develop neurodegenerative disease [4]. Moreover, overexpression of huntingtin protects striatal cells from a variety of apoptotic stimuli [5]. Huntingtin becomes toxic when it contains an abnormal polyQ expansion. PolyQ-huntingtin induces the formation of neuritic and intranuclear inclusions, neuronal dysfunction and finally neuronal death. The precise mechanisms underlying these phenomena are not well understood and it is not known how increased neuronal death in the brain relates to huntingtin function and dysfunction. Recent evidences suggest that huntingtin is involved in intracellular transport. Indeed, cytoplasmic huntingtin colocalizes with microtubules [6] and interacts with ß-tubulin [7]. 0369-8114/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.patbio.2004.12.008
It also interacts with huntingtin-associated protein 1 (HAP1), which is implicated in trafficking, huntingtin-interacting proteins 1 and 14 (HIP1 and HIP14), which are involved in endocytosis and trafficking, and PACSIN1 (protein kinase C and casein kinase substrate in neurons1), which is involved in endocytosis [8–12]. Here, we will review recent studies demonstrating that huntingtin plays a role in intracellular transport and that the alteration of this process results in HD. We will also discuss the general importance of transport in neurodegenerative disorders.
2. Intracellular transport and neurons Neurons are highly polarized cells composed of a cell body and an extensive network of cell processes: dendrites and a single axon. The axonal extension can reach up to one meter in length. Most protein synthesis is restricted to the cell body. Therefore, active transport is required to supply the axon with the newly synthesized material. Conversely, external signals have to be transmitted to the cell body, where the signaling cascade is activated. Here also, active transport of receptor/ligand complexes is required for a quick and appropriate response [13,14]. Due to the length of their processes, transport efficiency is of particular importance in neurons. To allow efficient communication between cell bodies and axon termini, molecular motor proteins continuously shuttle vesicles and organelles along the microtubules and actin filaments that make up the cellular cytoskeleton. This transport process mostly involves microtubules, which are polarized structures with “plus” (cell extremity) and “minus” (cell body) ends. Molecular motors are considered to be unidirectional:
190
Editorial / Pathologie Biologie 53 (2005) 189–192
dynein complexes are connected to retrograde transport (from plus to minus end), whereas kinesins are connected to anterograde transport (from cell body to plasma membrane) [15–18]. These two classes of motor complexes are required for efficient transport in neurons. Disruption of these complexes has dramatic consequences on neurons and leads to severe diseases.
3. Huntingtin and transport In Drosophila, a reduction in huntingtin protein expression causes axonal transport defects in larval nerves and neurodegeneration in adult eyes [19]. This strongly supports the hypothesis that huntingtin plays a crucial role in intracellular trafficking. Indeed, Gauthier et al. [20] demonstrate that huntingtin plays a role in the intracellular transport of brainderived neurotrophic factor (BDNF). Why study BDNF? BDNF is an important factor in HD. It is produced in the cortex and transported to the striatum, the major site of degeneration in HD, where it supports neuronal differentiation and survival. It inhibits polyQ-huntingtininduced neuronal death and its level is abnormally low in HD patients. This low level is partly due to a decreased BDNF gene transcription in the disease situation [21]. Gauthier et al. show that BDNF transport from the cortex to the striatum is also altered in disease and demonstrate that huntingtin plays a stimulatory role in axonal transport. Normal full-length huntingtin stimulates BDNF transport. The mutant form has lost this ability, leading to reduced BDNF support and thus to increasing susceptibility of striatal neurons to death. This phenotype is mediated by HAP1, which interacts with huntingtin and with the p150Glued subunit of dynactin. Huntingtin normally interacts with p150Glued via HAP1 and stimulates BDNF transport. In contrast, when huntingtin contains an abnormal polyQ expansion, it interacts more strongly with HAP1 and p150Glued, leading to the detachment of the molecular motors from the microtubules and thus to less efficient transport of BDNF vesicles.
and terminals [25]. What are the consequences of these aggregates on axonal transport? N-terminal huntingtin polypeptide fragments containing the polyQ expansion cause axonal transport defects [19,26–28], which subsequently induce neuronal death. Alteration in transport could be due to a physical blockage of vesicles but could also involve the titration by mutant huntingtin aggregates of motor proteins (particularly p150Glued and kinesin heavy chain) from other cargoes and pathways. In conclusion, in early stages of the disease, the role of huntingtin in transport is lost following the disruption of the huntingtin (soluble form)/HAP1 interaction. In later stages, polyQ-huntingtin forms neuritic aggregates that contribute to a trafficking defect by a gain of function mechanism.
5. Disruption of cellular transport: a common phenomenon in neurodegenerative disorders Transport defects have also been described in other polyQ neurodegenerative disorders. The polyQ-containing androgen receptor (AR), responsible for spinobulbar muscular atrophy (SBMA), inhibits fast axonal transport [26,29]. Non polyQ neurodegenerative diseases have also been linked to transport failure. In Alzheimer’s disease (AD), the amyloid precursor protein (APP), responsible for familial forms of AD, disrupts axonal transport [30]. Similarly, overexpression of tau, a neuronal microtubule-associated protein that accumulates in AD, blocks organelle trafficking [31]. Several different neurodegenerative disorders are caused by mutation within motor proteins. For instance, Charcot–Marie–Tooth disease type 2 is caused by a loss-of-function mutation in the kinesin KIF1B [32], and hereditary spastic paraplegia type 10 is caused by a missense mutation in KIF5A [33]. Finally, a mutation in p150Glued subunit of dynactin has been identified in a family with an autosomal dominant form of lower motor neurons disease [34]. In agreement, inhibition of dynein-mediated axonal transport causes neurodegeneration in mice models [35,36].
4. PolyQ aggregates and transport
6. Concluding remarks
The study by Gauthier et al. demonstrates that at least part of the anti-apoptotic properties of huntingtin are linked to its stimulatory effect on the transport of BDNF, a key neurotrophic factor. They also show that loss of the BDNF transport function by huntingtin may be an early step in HD. Another critical step in HD pathogenesis is the cleavage of polyQ-huntingtin into N-terminal fragments containing the polyQ expansion. These fragments translocate into the nucleus and induce the formation of aggregates [22]. In the nucleus, polyQ-huntingtin fragments cause neuronal death by a gain of function leading to the dysregulation of transcriptional activity [23,24]. In addition, N-terminal huntingtin fragments and their aggregates accumulate in axonal processes
Slowing of transport might be a general phenomenon in neurodegenerative diseases. It can be either causative or contributory depending on the disease. Neurons are highly susceptible to dysregulation of transport. Indeed, as transport in neurons occurs over very long distances, a decrease in intracellular trafficking has dramatic consequences on their viability. The development of accurate models of intracellular transport in neurons should therefore help to understand the molecular mechanisms underlying these diseases. Axonal transport is a promising target for designing and testing treatments to slow or to block neurodegeneration. In the case of HD, compounds that enhance transport or rescue huntingtin dysfunction might be of therapeutic interest as hun-
Editorial / Pathologie Biologie 53 (2005) 189–192
191
tingtin directly controls transport of the pro-survival factor BDNF. This is of utmost importance, as no treatment currently exists for this devastating disorder.
[12] Modregger J, DiProspero NA, Charles V, Tagle DA, Plomann M. PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington’s disease brains. Hum Mol Genet 2002;11:2547–58.
Acknowledgements
[13] Kuruvilla R, Zweifel LS, Glebova NO, Lonze BE, Valdez G, Ye H, et al. A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling. Cell 2004;118:243–55.
We thank members of the Saudou/Humbert’s laboratory for helpful comments. Our work is supported by grants from CNRS, Association pour la Recherche sur le Cancer (ARC no. 4807), Fondation pour la Recherche Médicale and Fondation BNP Paribas, Association Francaise contre les Myopathies (AFM), Provital/P. Chevalier, Hereditary Disease Foundation Cure HD Initiative and HighQ Foundation to F.S. and S.H. B.C.C. was supported by Hereditary Disease Foundation Cure HD Initiative and is currently funded by Association pour la Recherche sur le Cancer. F.S. is recipient of an EMBOYoung Investigator award and an Inserm/AP-HP investigator. S.H. is an Inserm investigator.
[14] Heerssen HM, Pazyra MF, Segal RA. Dynein motors transport activated Trks to promote survival of target-dependent neurons. Nat Neurosci 2004;7:596–604.
References
[20] Gauthier LR, Charrin BC, Borrell-Pagès M, Dompierre JP, Rangonne H, Cordelières FP, et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular trannsport along microtubules. Cell 2004;118:127–38.
[1]
Martin JB, Gusella JF. Huntington’s disease. Pathogenesis and management. N Engl J Med 1986;315:1267–76.
[2]
Rangone H, Humbert S, Saudou F. Huntington’s disease: how does huntingtin, an anti-apoptotic protein, become toxic? Pathol Biol (Paris) 2004;52:338–42.
[3]
Zeitlin S, Liu JP, Chapman DL, Papaioannou VE, Efstratiadis A. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat Genet 1995;11: 155–63.
[4]
[5]
[6]
[7]
Dragatsis I, Levine MS, Zeitlin S. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet 2000;26:300–6. Rigamonti D, Sipione S, Goffredo D, Zuccato C, Fossale E, Cattaneo E. Huntingtin’s neuroprotective activity occurs via inhibition of procaspase-9 processing. J Biol Chem 2001;276:14545–8. Gutekunst CA, Levey AI, Heilman CJ, Whaley WL, Yi H, Nash NR, et al. Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. Proc Natl Acad Sci USA 1995;92:8710–4. Hoffner G, Kahlem P, Djian P. Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: relevance to Huntington’s disease. J Cell Sci 2002; 115:941–8.
[8]
Li XJ, Li SH, Sharp AH, Nucifora Jr. FC, Schilling G, Lanahan A, et al. A huntingtin-associated protein enriched in brain with implications for pathology. Nature 1995;378:398–402.
[9]
Kalchman MA, Koide HB, McCutcheon K, Graham RK, Nichol K, Nishiyama K, et al. HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain. Nat Genet 1997;16:44–53.
[10] Wanker EE, Rovira C, Scherzinger E, Hasenbank R, Walter S, Tait D, et al. HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system. Hum Mol Genet 1997;6:487–95. [11] Singaraja RR, Hadano S, Metzler M, Givan S, Wellington CL, Warby S, et al. HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis. Hum Mol Genet 2002;11:2815–28.
[15] Vallee RB, Hook P. Molecular motors: a magnificent machine. Nature 2003;421:701–2. [16] Vale RD. The molecular toolbox for intracellular transport. Cell 2003; 112:467–80. [17] Hirokawa N, Takemura R. Kinesin superfamily proteins and their various functions and dynamics. Exp Cell Res 2004;301:50–9. [18] Hirokawa N. Kinesin and dynein superfamily proteins and the mechanism of organelle transport. Science 1998;279:519–26. [19] Gunawardena S, Her LH, Brusch RG, Laymon RA, Niesman IR, Gordesky-Gold B, et al. Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 2003;40:25–40.
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Bénédicte C. Charrin Frédéric Saudou * Sandrine Humbert * UMR 146 CNRS/Institut Curie, Bldg. 110, Centre Universitaire, 91405 Orsay cedex, France E-mail address: [email protected] (F. Saudou). E-mail address: [email protected] (S. Humbert). Received 29 November 2004; accepted 9 December 2004 Available online 22 January 2005 * Corresponding authors.