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Figure 1.
Microtubule-based transport within the axon. The plus-end motor kinesin transports cargoes anterogradely while those that need to be brought back to the cell body are transported by the minus-end motor dynein and some kinesins.

Microtubule-based transport within the axon. The plus-end motor kinesin transports cargoes anterogradely while those that need to be brought back to the cell body are transported by the minus-end motor dynein and some kinesins.

Figure 2.
Disruption of transport within narrow-caliber, long axons could lead to stalling of vesicles and formation of cytoplasmic inclusions within axonal processes, which may ultimately lead to neuronal death and dysfunction. Thus, accumulation of organelles within axonal processes may instigate an early neurodegenerative disease pathway.

Disruption of transport within narrow-caliber, long axons could lead to stalling of vesicles and formation of cytoplasmic inclusions within axonal processes, which may ultimately lead to neuronal death and dysfunction. Thus, accumulation of organelles within axonal processes may instigate an early neurodegenerative disease pathway.

Table. 
PolyQ Diseases
PolyQ Diseases
1.
Zhao  CTakita  JTanaka  Y  et al.  Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bβ. Cell 2001;105587- 597
PubMedArticle
2.
Reid  EKloos  MAhley-Koch  A  et al.  A kinesin heavy chain (KIF5A) mutation in hereditary spastic paralegia (SPG10). Am J Hum Genet 2002;711189- 1194
PubMedArticle
3.
LaMonte  BHWallace  KEHolloway  BA  et al.  Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron 2002;34715- 727
PubMedArticle
4.
Williamson  TLCleveland  DW Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci 1999;250- 56
PubMedArticle
5.
Puls  IJonnakuty  CLaMonte  BH  et al.  Mutant dynactin in motor neuron disease. Nat Genet 2003;33455- 456
PubMedArticle
6.
Hafezparast  MKlocke  RRuhrberg  C  et al.  Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 2003;300808- 812
PubMedArticle
7.
Kamal  AStokin  GYang  ZXia  CHGoldstein  LS Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron 2000;28449- 459
PubMedArticle
8.
Gunawardena  SGoldstein  LS Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in DrosophilaNeuron 2001;32389- 401
PubMedArticle
9.
Kamal  AAlmenar-Queralt  ALeBlanc  JFRoberts  EAGoldstein  LS Kinesin-mediated axonal transport of a membrane compartment containing β-secretase and presenilin-1 requires APP. Nature 2001;414643- 648
PubMedArticle
10.
Takashima  AMurayama  MMuryama  O  et al.  Presenilin 1 associates with glycogen synthase kinase-3β and its substrate tau. Proc Natl Acad Sci U S A 1998;959637- 9641
PubMedArticle
11.
Pigino  GMorfini  GPelsman  AMattson  MPBrady  STBusciglio  J Alzheimer’s presenilin-1 mutations impair kinesin-based axonal transport. J Neurosci 2003;234499- 4508
PubMed
12.
Morfini  GSzebenyi  GElluru  RRatner  NBrady  ST Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J 2002;21281- 293
PubMedArticle
13.
Evert  BOWullner  UKlockgether  T Cell death in polyglutamine diseases. Cell Tissue Res 2000;301189- 204
PubMedArticle
14.
Wanker  EE Protein aggregation and pathogenesis of Huntington’s disease: mechanism and correlations. Biol Chem 2000;381937- 942
PubMedArticle
15.
Kuemmerle  SGutekunst  CAKlein  AM  et al.  Huntington aggregates may no predict neuronal death in Huntington’s disease. Ann Neurol 1999;46842- 849
PubMedArticle
16.
Tarlac  VStorey  E Role of proteolysis in polyglutamine disorders. J Neurosci Res 2003;74406- 416
PubMedArticle
17.
Menalled  LBSison  JDWu  J  et al.  Early motor dysfunction and striosomal distribution of huntingtin microaggregates in Huntington’s disease knock-in mice. J Neurosci 2002;228266- 8276
PubMed
18.
Watase  KWeeber  EJXu  B  et al.  A long CAG repeat in the mouse SCA1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron 2002;34905- 919
PubMedArticle
19.
Yoo  SYPennesi  MEWeeber  EJ  et al.  SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Neuron 2003;37383- 401
PubMedArticle
20.
Chen  SBerthelier  VYang  WWetzel  R Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity. J Mol Biol 2001;311173- 182
PubMedArticle
21.
Piccioni  FPinton  PSimeoni  S  et al.  Androgen receptor with elongated polyglutamine tract forms aggregates that alter axonal trafficking and mitochondrial distribution in motor neuronal processes. FASEB J 2002;161418- 1420
PubMed
22.
Li  HLi  SHJohnston  HShelbourne  PFLi  XJ Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nat Genet 2000;25385- 389
PubMedArticle
23.
Li  HLi  SHYu  ZXShelbourne  PLi  XJ Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington's disease mice. J Neurosci 2001;218473- 8481
PubMed
24.
Klement  IASkinner  PJKaytor  MD  et al.  Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 1998;9541- 53
PubMedArticle
25.
Gunawardena  SHer  LBrusch  RG  et al.  Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in DrosophilaNeuron 2003;401- 2
PubMedArticle
26.
Trushina  EHeldebrant  MPPerez-Terzic  CM  et al.  Microtubule destabilization and nuclear entry are sequential steps leading to toxicity in Huntington's disease. Proc Natl Acad Sci U S A 2003;10012171- 12176
PubMedArticle
27.
Li  SHGutekunst  CAHersch  SMLi  XJ Interaction of huntingtin-associated protein with dynactin P150Glued. J Neurosci 1998;181261- 1269
PubMed
28.
Block-Galarza  JChase  KOSapp  E  et al.  Fast transport and retrograde movement of huntingtin and HAP 1 in axons. Neuroreport 1997;82247- 2251
PubMedArticle
29.
DiFiglia  MSapp  EChase  K  et al.  Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 1995;141075- 1081
PubMedArticle
30.
DiFiglia  MSapp  EChase  KO  et al.  Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997;2771990- 1993
PubMedArticle
31.
Gunawardena  SGoldstein  LS Cargo-carrying motor vehicles on the neuronal highway: transport pathways and neurodegenerative disease. J Neurobiol 2004;58258- 271
PubMedArticle
32.
Li  XSharp  AHLi  SHDawson  TMSnyder  SHRoss  CA Huntingtin-associated protein (HAP1): discrete neuronal localizations in the brain resemble those of neuronal nitric oxide synthase. Proc Natl Acad Sci U S A 1996;934839- 4844
PubMedArticle
33.
Engelender  SSharp  AHColomer  V  et al.  Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Hum Mol Genet 1997;62205- 2212
PubMedArticle
34.
Stowers  RSMegeath  LJGorska-Andrzejak  JMeinertzhagen  IASchwarz  TL Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein. Neuron 2002;361063- 1077
PubMedArticle
35.
Sapp  EPenney  JYoung  AAronin  NVonsattel  JPDiFiglia  M Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease. J Neuropathol Exp Neurol 1999;58165- 173
PubMedArticle
36.
Hurd  DDSaxton  W Kinesin mutations cause motor neuron disease phenotypes by disrupting fast axonal transport in DrosophilaGenetics 1996;1441075- 1085
PubMed
37.
Cattaneo  ERigamonti  DGoffredo  DZuccato  CSquitieri  FSipione  S Loss of normal huntingtin function: new developments in Huntington's disease research. Trends Neurosci 2001;24182- 188
PubMedArticle
38.
Gauthier  LRCharrin  BCBorrell-Pages  M  et al.  Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 2004;118127- 138
PubMedArticle
39.
Szebenyi  GMorfini  GABabcock  A  et al.  Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 2003;4041- 52
PubMedArticle
40.
Yang  QHashizume  YYoshida  M  et al.  Morphological Purkinje cell changes in spinocerebellar ataxia type 6. Acta Neuropathol (Berl) 2000;100371- 376
PubMedArticle
41.
Lee  WCYoshihara  MLittleton  JT Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease. Proc Natl Acad Sci U S A 2004;1013224- 3229
PubMedArticle
42.
Bates  GPHockly  E Experimental therapeutics in Huntington’s disease: are models useful for therapeutic trials? Curr Opin Neurol 2003;16465- 470
PubMed
Basic Science Seminars in Neurology
January 2005

Polyglutamine Diseases and Transport ProblemsDeadly Traffic Jams on Neuronal Highways

Author Affiliations

Author Affiliations: Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla.

 

HASSAN M.FATHALLAH-SHAYKHMD

Arch Neurol. 2005;62(1):46-51. doi:10.1001/archneur.62.1.46
Abstract

The expansion of CAG repeats encoding glutamine (polyQ) causes, to date, 9 late-onset progressive neurodegenerative disorders, including Huntington disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxias 1, 2, 3, 6, 7, and 17. Although many studies using both knockout and transgenic mouse models suggest that a toxic gain of function is central to neuronal dysfunction, the exact mechanisms of neurotoxic effects remain elusive. Protein aggregations within neurons seem to be a common manifestation in almost all polyQ diseases, and such accumulations are perhaps major triggers of cellular stress and neuronal death. Recent data lead to the tantalizing proposal that disruption of axonal transport pathways within long, narrow-caliber axons could lead to protein accumulations that can elicit neuronal death, ultimately causing a neuronal dysfunction pathway observed in polyQ expanded diseases. Perhaps perturbations in transport pathways are an early event involved in instigating polyQ disease pathology.

Our nervous system can be thought of as requiring a transport system composed of highways that transport essential cargoes from a central station, cell bodies in the spinal cord or brain, to places of need, nerve terminals or synapses, very much like a busy freeway system. Most materials within axons or synapses are synthesized within the neuronal cell body and are moved along lengthy axons to sites of function. Molecular motors, such as kinesin and dynein, are proteins that power cargo transport and use adenosine triphosphate hydrolysis to move vital cargoes on microtubule tracks (Figure 1). Within axons, organelles, vesicles, cytoskeletal proteins, signaling molecules, and other supplies from the cell body are transported by kinesin motors in the anterograde direction to nerve terminals and synapses, while signaling molecules and other components that need to be returned to the cell body from synapses are transported in the retrograde direction by dynein and some kinesin motors. Since transport of cargoes is required for cell viability, it is conceivable that disruption in this long distance transport system can lead to disease pathology observed in many neurodegenerative diseases, including polyglutamine (polyQ) diseases.

AXONAL TRANSPORT PATHWAYS AND NEURODEGENERATIVE DISEASE

The importance of the axonal transport system in disease states has been recently highlighted by several intriguing studies. These studies not only suggest that strangulation of the axon may led to disease pathology but also implicate components of the axonal transport machinery as targets for the development of human disease. Mutations in KIF1Bβ result in Charcot-Marie-Tooth disease type 2A, which is characterized by progressive dysfunction of peripheral neurons, possibly owing to the reduced transport of synaptic vesicle precursors.1 A missense mutation in the neuronal kinesin heavy chain gene KIF5A results in hereditary spastic paraplegia, a condition that arises owing to axonal degeneration of motor and sensory neurons at the distal ends of the longest axons of the central nervous system.2 In a dynamitin (a component of the dynactin complex that interacts with dynein) overexpressing mouse model,3 excess dynamitin disassembles dynactin and inhibits retrograde transport, suggesting that impediment of axonal transport is sufficient to cause motor neuron degeneration observed in amyotrophic lateral sclerosis. While mice with transgenic amyotrophic lateral sclerosis showed abnormalities in microtubule-based transport, with decreased rates of slow axonal transport and degeneration of motor neurons,4 the dynamitin transgenic mice demonstrate a late-onset progressive motor neuron degenerative disease.3 A mutation in the human dynactin gene DCTN1 causes human motor neuron disease,5 and missense mutations in cytoplasmic dynein heavy chain (Dnchc1) cause selective impairment of axonal retrograde transport, cell death, Lewy body–like inclusions, and progressive motor neuron degeneration.6 Together, these studies argue that axonal transport failure can be a causative feature in neurodegenerative disease, strengthening the proposal that disruption of axonal transport is an important determinant in the initiation and perhaps the progression of pathogenesis.

Axonal transport problems have also been implicated in Alzheimer disease (AD). Recent work from our laboratory demonstrates that the amyloid precursor protein (APP) can function as a kinesin-I receptor.7,8 In Drosophila overexpression of wildtype human APP or familial mutations responsible for AD (Swedish and London) cause axonal vesicle accumulations, which contain APP and trigger neuronal cell death.8 Secretases (β-secretase and presenilin [PS]) that are responsible for the generation of pathogenic amyloid-β (Aβ) appear to be present in APP vesicles.9 Perhaps axonal blockages containing APP vesicles are sites of Aβ production, and processing of APP within these sites leads to the dissociation of kinesin from APP vesicles leading to the failure of transport within narrow axons, thus triggering the induction of neuronal dysfunction or death.

Yet another link between AD and axonal transport problems comes from the observation that PS, a component of the γ-secretase complex, interacts with GSK3β.10 An enhancement in GSK3β activation and a deficiency in kinesin-1–mediated transport were observed in PS mutations that cause familial AD (FAD).11 Intriguingly, GSK3β phosphorylates kinesin light chains leading to the dissociation of kinesin from membranes.12 Perhaps the disassociation of kinesin from APP-PS–containing vesicles results in the failure of transport in FAD-PS mutants. Together, these observations suggest that the axonal transport pathway may be central to the pathogenesis observed in AD.

Disruptions in transport pathways could also be involved in the pathogenesis of Huntington disease (HD) and other polyQ expansion diseases. Since protein aggregates are a common feature in all polyQ diseases, it is conceivable that failure in the transport system may also result in polyQ pathogenesis. Herein we briefly highlight polyQ disease pathology and discuss several recent advances relating this pathology to possible transport problems.

PolyQ PROTEINS AND DISEASE PATHOLOGY

Polyglutamine repeat diseases are a class of hereditary neurodegenerative diseases caused by the expansion of CAG triplet repeats encoding a polyglutamine tract in the normal protein (Table). These disorders are progressive, dominantly inherited (except for spinobulbar muscular atrophy), typically begin in midlife, and result in severe neuronal dysfunction and neuronal cell death. The expanded trinucleotide repeats are unstable, with increased repeat length correlating with worsening of the disease phenotype. The polyQ expansion is believed to confer a toxic gain of function, perhaps causing an increased propensity for the mutant protein to misfold and aggregate. Although all 9 polyQ diseases are genetically distinct and can be characterized by their specific lesion distributions in the nervous system, recent studies indicate that except for spinocerebellar ataxia (SCA) types 2 and 6, the formation of intranuclear inclusions within neurons is a common hallmark of all 9 diseases. Nuclear inclusions have been found in neuronal populations susceptible to the disease process, and this has lead to the widespread belief that intranuclear aggregations are central to polyQ pathogenesis.

Clinically, polyQ disorders share several common features, including slow progression and late (adult) onset. They also exhibit anticipation, becoming earlier and/or more severe in succeeding generations, which is correlated with an intergenerational increase in repeat length. Each of the polyQ disorders affect specific but overlapping regions of the brain. The clinical pathologic features of spinobulbar muscular atrophy is relatively distinct, whereas that of dentatorubral-pallidoluysian atrophy overlaps HD, and SCAs (reviewed in Evert et al13). Involuntary movements, intellectual impairment, and emotional disturbances clinically characterize HD, while spinobulbar muscular atrophy is a rare progressive neuromuscular disorder characterized by proximal weakness, atrophy, and fasciculations. Dentatorubral-pallidoluysian atrophy is characterized by progressive dementia, myoclonic epilepsy, cerebellar ataxia, and choreoathetotic movements. All SCAs exhibit variable degrees of cerebellar and brainstem degeneration accompanied by progressive cerebellar ataxia associated neurological signs including ophthalmoplegia, dementia, and extrapyramidal signs.

At the molecular level, polyQ disease proteins are expressed ubiquitously throughout the brain and other tissues, although the normal function of most of these proteins remains unknown (Table). Exceptions are the androgen receptor in spinobulbar muscular atrophy, the P/Q-type calcium channel subunit in SCA6, and, based on recent work the huntingtin protein. Except for SCA3, the polyQ tract is located toward the N-terminal region of the protein in all polyQ diseases. Apart from the polyQ tract, the polyQ proteins do not share any other common features. In the case of SCA3 and HD, cleavage of the mutant protein is thought to promote aggregation.

VIEWS OF NEUROTOXIC EFFECTS IN PolyQ DISEASE

Although little is known about the mechanism by which polyQ expansion leads to pathogenesis, one proposal is that misfolding of the mutant protein triggers a cascade of events, which ultimately leads to disease pathology (reviewed in Evert et al13). The misfolded protein may undergo proteolytic cleavage, interact with other proteins, self-aggregate, and these aggregates may later translocate into the nucleus. Although the propensity of polyQ proteins to aggregate is a common feature observed in all 9 polyQ expansion diseases, it remains unclear whether aggregates, which contain not only mutant protein but components of the ubiquitin-proteosome pathway, chaperones, transcriptional regulators, and other polyQ-containing proteins, are the cause of pathogenesis or the end result of a cascade of events. Indeed, Wanker14 postulates that aggregates themselves are neurotoxic even though the distribution of aggregates within the central nervous system does not completely match areas of neuronal loss.15

Whatever the cause, most proposals for disease mechanism include the hypothesis that aggregates alone are a precondition of neurotoxic effects, and several models propose that dysfunction originates from aggregate formation (reviewed in Tarlac and Storey16): (1) Sequestration of cellular factors away from their usual locations into aggregates are proposed to compromise their function and cause toxic effects; (2) recruitment of transcription factors into aggregates are proposed to attenuate transcription factor function; and (3) accumulation of molecular chaperones and proteosomes into aggregates are proposed to limit their availability in the cell, leading to diminished clearance and harmful accumulation of misfolded or damaged proteins, eventually activating cellular stress response pathways and inducing apoptosis.

In contrast, however, many recent studies propose that neuronal dysfunction occurs before aggregate formation. Prior to the detection of aggregates, neuronal and behavioral problems were detected in knock-in HD mice with 94 CAG repeats,17 in SCA1 mice with 154 CAG repeats,18 and in SCA7 mice with 266 CAG repeats.19 Indeed, another model suggests that aggregation of polyQ proteins may initially function as beneficial “sinks” that activate degradation pathways, which may later become defective owing to overactivation, ultimately resulting in neuronal dysfunction.20 Since ubiquitin and components of the proteosome were observed to colocalize with aggregates, further aggregation of polyQ proteins might block the degradation pathway.

An important point of controversy is whether neuronal toxic effects observed in polyQ diseases results from nuclear or cytoplasmic events. The most common type of aggregates observed in polyQ disease are intranuclear, but these may occur later in disease progression owing to problems or failures in other pathways. Indeed, neuropil aggregates were observed with expanded polyQ repeats in the context of the androgen receptor21 in transgenic HD mice and in HD-affected patient brains before the onset of clinical problems.22,23 Similarly, Klement et al24 demonstrate that while nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 is not required for initial pathogenesis in transgenic SCA1 mice. Consistent with these findings are recent results demonstrating that both cytoplasmic and nuclear accumulation pathways can independently lead to neuronal dysfunction25 and that cytoplasmic accumulations precede nuclear inclusions.26 Thus, cytoplasmic accumulations may be the primary events in toxic effects. However, it is still unknown if protein cleavage plays a role, and if aberrant cleavage of N-terminal fragments containing pathogenic polyQ repeats are the cause of cytoplasmic inclusion formation and disease pathology. Perhaps the cytoplasmic accumulations observed within axons are sites of N-terminal cleavage, and these pathogenic N-terminal fragments then promote nuclear entry and activate transcriptional processes, which may lead to nuclear-mediated toxic events.22,25,27

Viewed broadly, an intriguing feature of polyQ disease is that while disease-causing genes are widely expressed (Table), only neurons are affected. These observations raise the question of whether the specificity observed is due to the nature of the neuron, with its long narrow axonal and dendritic processes. Essential components must be transported over great distances in axons and dendrites along microtubule tracks for cell viability. Perhaps defects in this transportation system have long-term effects on polyQ disease pathology.

CAN AXONAL TRANSPORT DEFECTS CAUSE PolyQ DISEASE PATHOLOGY?

Although genes encoding motor proteins may be key players in human diseases when mutated, it is possible that proteins that regulate or interact with motor proteins may also cause disease when mutated. Alternatively, abnormal interactions of proteins not normally functioning in transport could cause transport problems subsequently leading to neuronal defects. Indeed, the widespread occurrence of axonal (or dendritic) inclusions observed in polyQ diseases raises the possibility that perturbations of transport pathways are an early susceptibility factor in disease pathology. In fact, new work leads to the proposal that stalling of vesicles within narrow caliber axons triggers aggregate formation within axons, which could then initiate a cascade of events, resulting in neuronal death and dysfunction (Figure 2).25 There are 2 complementary aspects to this proposal: (1) disease-causing proteins may have normal functions in the axonal transport system and may cause axonal blockages when altered; and (2) “sticky” diseased proteins may physically block transport within narrow axonal processes, and also titrate normal proteins, instigating pathways that lead to subsequent neuronal problems.

Many observations support these proposals for HD. In 1997, Block-Galarza et al28 showed that huntingtin, the protein that causes HD, was transported both anterogradely and retrogradely in rat sciatic nerve axons. Immunolocalization studies in human and rat brains revealed cytoplasmic huntingtin within neurons, and biochemical analyses indicated that huntingtin was enriched in compartments containing vesicle-associated proteins.29,30 Recently our laboratory found that normal Drosophila huntingtin functions in the axonal transport pathway, perhaps to transport a subclass of vesicles.25 Although how huntingtin associates with the axonal transport machinery is still unclear, it can be proposed that huntingtin may associate with motor proteins via HAP1, a protein that has been shown to interact with both huntingtin and the p150 subunit of dynactin,27 thereby enabling retrograde transport and perhaps anterograde transport.31 HAP1 itself is transported both anterogradely and retrogradely and also associates with vesicles and with microtubules.28,32,33 Intriguingly, mutations in the Drosophila HAP1-like protein, Milton, causes axonal transport defects and may function in the transport of mitochondria to synapses by binding to kinesin.34 Thus huntingtin and HAP1 may have vital roles in axonal transport and perhaps with dynactin they have a role in establishing bidirectional transport.

Pathologic evidence for axonal transport problems in HD comes from observations in transgenic HD mouse models and human patient brains. Several groups have demonstrated that dystrophic striatal and corticostriatal neurites in HD exhibit characteristics of blocked axons, namely, accumulations of vesicles and organelles in swollen axonal projections and termini in association with huntingtin aggregates.30,35 Huntingtin accumulations have been found in axons of striatal projection neurons in R6/2 and knockin mouse models of HD and in human patient brains.23 These striatal axonal inclusions are better correlated with striatal neuronal loss than the presence of nuclear inclusions. Intriguingly, the axonal pathology observed in striatal neurons is virtually identical to the phenotype of motor protein mutants in Drosophila and polyQ-induced axonal blockages found in Drosophila models of polyQ disease.25,36

Although little is known about how these phenotypes arise and whether these observations are an early indication of neurodegeneration or the initial step in a cascade of events that cause dysfunction, these findings together with the evidence for cytosolic localization of full-length huntingtin protein and its association with cytoskeletal and vesicular structures are compelling arguments for a role of axonal transport in the pathology of HD. Since mutant huntingtin was shown to interfere with its anterograde transport, contributing to the depletion of brain-derived neurotrophic factor in the striatum,37 perhaps normal huntingtin is required for efficient vesicle trafficking of cortical brain-derived neurotrophic factor. Indeed, a recent study supports this proposal.38

A similar mechanism can be proposed for other polyQ diseases. Expression of expanded polyQ repeats in the context of the androgen receptor also causes neuropil aggregates and alters the distribution of kinesin.21 Consistent with this, recent data from Szebenyi et al39 demonstrate a polyQ length-dependent inhibition of anterograde and retrograde transport in isolated squid axoplasm by truncated versions of huntingtin or the androgen receptor. In SCA6, axonal accumulations are observed that appear to contain accumulations of neurofilaments and other materials that fail to be transported.40 In addition, expression of different pathogenic polyQ proteins within Drosophila neurons cause axonal blockages, which increase with reductions in motor proteins and reduce the amount of motor proteins available for normal transport.25 These observations suggest that accumulations of disease proteins, perhaps those that are sticky, can physically block transport pathways and titrate motors proteins away from their normal functions within narrow- caliber axons or dendritic processes. Consistent with this idea, it was recently shown that cytoplasmic huntingtin aggregates trap or titrate polyQ proteins, which may further block transport pathways.41 Thus, the 2 pathogenic pathways suggested by the transport hypothesis (described earlier) may not be mutually exclusive.

Although transport problems cannot account for all aspects of polyQ disease pathology, they provide a plausible explanation for how failures in the transport system could result in neuronal loss. Future experiments should focus on investigating axonal transport problems in other polyQ diseases for which excellent animal models are available and for which human tissues are readily accessible. Since different motor proteins move a variety of cargoes, including membrane organelles, protein complexes, complexes of nucleic acids, signaling molecules, neuroprotective and repair molecules and cytoskeletal complexes along microtubule tracks, the susceptibility of different neurons to different polyQ disease may result owing to the specialized function of the normal protein within those neurons. Thus, rigorous investigations are needed to elucidate the normal functions of proteins involved in polyQ diseases, in particular to determine if these are involved in the axonal transport pathway.

EXPERIMENTAL THERAPEUTICS AND THEIR EFFECT ON AXONAL TRANSPORT AND PolyQ DISEASE PATHOLOGY

Although it is still not understood how polyQ disease pathology is caused, several groups have focused on identifying chemical agents that modulate cell toxicity or aggregation in a variety of polyQ disease models including yeast, Caenorhabditis elegans, Drosophila, and mouse (reviewed in Bates and Hockly42). Current potential therapeutic interventions targeting specific molecular events include minocycline (a caspase 1 inhibitor), cystamine (an inhibitor of tissue transglutaminase), Congo red (an inhibitor of polyQ aggregation), and suberoylanilide hydroxamic acid (a hydroxamic acid inhibitor) (reviewed in Bates and Hockly42). It is still unknown if these compounds act on the target for which they were selected. While it is important to distinguish if transport failures are an early secondary problem as opposed to being the true initiating cause of polyQ disease, pharmacological interventions directed toward the transport process may be valuable in the development of therapies. An important first step is to test if any of the above compounds prevent axonal transport problems in the in vivo Drosophila model system, which exhibits specific axonal transport phenotypes within polyQ expressing neurons.25 Ultimately, it is critical to develop axonal transport assays in living patients.

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Article Information

Correspondence: Lawrence S. B. Goldstein, PhD, Howard Hughes Medical Institute, Cellular and Molecular Medicine West, Room 336, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0683 (lgoldstein@ucsd.edu).

Accepted for Publication: August 5, 2004.

Author Contributions:Study concept and design: Gunawardena and Goldstein. Analysis and interpretation of data: Gunawardena and Goldstein. Drafting of the manuscript: Gunawardena. Critical revision of the manuscript for important intellectual content: Gunawardena and Goldstein. Obtained funding: Goldstein. Administrative, technical, and material support: Gunawardena. Study supervision: Goldstein.

Funding/Support: This study was supported by a fellowship from the Wills Foundation, Houston, Tex, and by a senior postdoctoral fellowship from the Ellison Medical Foundation/American Federation for Aging Research (AFAR), New York, NY (Dr Gunawardena). Dr Goldstein is an investigator of the Howard Hughes Medical Institute, Chevy Chase, Md.

Acknowledgments: We apologize to those authors whose work was not cited owing to space limitations.

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