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Molecular genetics: Unmasking polyglutamine triggers in neurodegenerative disease

Key Points

  • Polyglutamine disorders involve an expanded stretch of CAG trinucleotides that encodes a glutamine tract in proteins specific for each disease. The discovery of this similarity among very heterogenous disorders has pointed to a shared mechanism for the initiation of the pathogenesis, which is probably related to the ability of the mutant protein to undergo self-aggregation, forming insoluble cellular inclusions.

  • In every polyglutamine disorder, the phenotype caused by the mutant allele is dominant. In addition, each disease shows a characteristic threshold for polyglutamine length below which symptoms do not occur. Above the threshold, there is a progressive decrease in onset age with polyglutamine length.

  • The discovery of the glutamine tract as a crucial element in triggering the pathological changes has led to the development of several transgenic mouse models of the different disorders. They have been designed either to reproduce the disease phenotype by the introduction of the mutant version of the human gene or to reproduce the genotype by introducing an equivalent mutation into the endogenous locus.

  • Mice that express the polyglutamine fragments of human huntingtin tend to show cellular inclusions analogous to those described in Huntington's disease. However, these animals do not show the whole phenotypic characteristics of the human pathology as, for instance, cell death is not observed. In fact, for neuronal loss to occur, expression of the full-length mutant protein is necessary.

  • Mice that encode an enlarged glutamine tract in the endogenous huntingtin gene do not develop profound neurological signs and, similarly, the formation of cellular inclusions is subtle and progresses very slowly. Therefore, these animals may be valuable for investigating the mechanism of initiation of the disorder, but are not likely to illuminate its final stages.

  • The genetic analysis of the polyglutamine disorders indicates that the development of therapeutic strategies should focus on four main points: first, the study of the abnormal conformation of the expanded glutamine tract; second, the identification of the targets first affected by the mutant protein; third, the examination of the biochemical changes downstream from the initiating process; and last, the replacement of lost tissue through neuronal transplantation.

Abstract

Two decades ago, molecular genetic analysis provided a new approach for defining the roots of inherited disorders. This strategy has proved particularly powerful because, with only a description of the inheritance pattern, it can uncover previously unsuspected mechanisms of pathogenesis that are not implicated by known biological pathways or by the disease manifestations. Nowhere has the impact of molecular genetics been more evident than in the dominantly inherited neurodegenerative disorders, where eight unrelated diseases have been revealed to possess the same type of mutation — an expanded polyglutamine encoding sequence — affecting different genes.

Main

Each polyglutamine disorder involves an expanded stretch of consecutive CAG trinucleotides that encodes a glutamine tract in a broadly expressed protein. These proteins are different for each disease, vary widely in size and harbour the glutamine segment at different locations (Box 1). SPINAL AND BULBAR MUSCULAR ATROPHY ( SMBA), characterized by progressive loss of anterior horn cells in the spinal cord and consequent progressive muscular weakness, is due to expansion of a normally POLYMORPHIC CAG repeat segment in the androgen receptor gene. Huntington's disease ( HD), known for its writhing, dance-like movement disorder and devastation of MEDIUM SPINY NEURONS in the striatum, is caused by a similar expansion near the 5′ end of a gene encoding huntingtin, a 350 kDa protein of unknown function. SPINOCEREBELLAR ATAXIAS (SCA) 1, 2, 3, 6 and 7 have all been associated with CAG expansions in unrelated genes, of which only one has a known function, the α1A-calcium channel subunit in SCA6. Interestingly, molecular analysis has also consolidated the classification of neurodegenerative disorders previously thought to be distinct on the basis of ancestry or geographic location. For example, Machado–Joseph disease ( MJD), which involves a progressive degeneration of spinocerebellar tracts with sparing of the inferior olive and cerebellar cortex, results from the same CAG expansion as SCA3. Similarly, dentatorubropallidoluysian atrophy ( DRPLA), a neurodegenerative disorder involving both ataxia and CHOREOATHETOSIS that is most common in Japan, was revealed to have the same molecular defect as Haw River syndrome ( HRS), a disorder in an African–American family from North Carolina.

The unsuspected relationship among these disparate disorders has indicated a shared mechanism for triggering pathogenesis which elicits pathways that culminate in selective cell loss. Unlike previous attempts to explain disease-associated neuropathology, which have been based on evaluation of the final pathology in the context of known biochemical and biological pathways, it is now possible to home in on the initiating events. These efforts need not rely on known pathways. Instead, they can be based on a firm knowledge of the trigger, that is, the genetic mutation, and can therefore be guided by fundamental genetic criteria, as defined by classic genotype–phenotype correlations.

Genetic criteria for the initiator of pathogenesis

In the investigation of any human disease, the patient provides the `gold standard' against which biochemical, cellular and animal models must be judged. The comparison of genotype (CAG repeat length) and consequent phenotype (age of onset and disease manifestations) as a structure–function assessment has been particularly informative in the polyglutamine disorders, because in each case a single type of mutation, varying only in severity, accounts for all individuals with the disorder. An important finding shared by the polyglutamine disorders is that the age of the person at neurological onset decreases with increased polyglutamine length (Fig. 1). Each disorder shows a characteristic threshold for glutamine tract length below which symptoms do not occur. Above the threshold, the progressive decrease in onset age with polyglutamine length shows a slightly different slope in each disorder, indicating that the increased severity due to each extra glutamine residue depends on protein context. These curves imply that in this class of inherited neurodegenerative disease, there is a common trigger of pathogenesis — the polyglutamine segment — which has different consequences depending on the protein in which it is contained. Most patients with polyglutamine diseases are heterozygous for the mutant allele, but in some cases disease homozygotes have been described, with two mutant alleles and no normal allele. The age of onset for people homozygous for the disease is primarily determined by the polyglutamine length encoded by the longer mutant allele. The impact of the second mutant allele in HD, SCA1 and SCA2, if there is any, cannot be discerned as it falls within the range of variation in onset age associated with typical heterozygotes1,2,3,4,5,6,7,8,9,10,11. In DRPLA and MJD/SCA3, and in some instances in SCA6, the second mutant allele acts to reduce the age at onset, although this effect is not as marked as the increase in severity caused by extra glutamines.

Figure 1: Relationship between age at onset and CAG repeat length for polyglutamine disorders.
figure1

Data compiled from the literature9,10,11,15,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98 were used to calculate the mean age at onset (denoted by `+') associated with various CAG repeat lengths and the best-fit curve (denoted by a smooth line), using a simple exponential decay model for the relationship, in each of the polyglutamine disorders. The age of onset of homozygotes for the various disorders is also shown (filled circles), plotted according to the longer of their two expanded CAG repeats. (DRPLA, dentatorubropallidoluysian atrophy; HD, Huntington's disease; MJD, Machado–Joseph disease; SBMA, spinal and bulbar muscular atrophy; SCA, spinocerebellar ataxia.)

In HD, the most prominent neuropathological consequence is the loss of neurons in the caudate and putamen, which begins in the tail of the caudate and progresses along caudo–rostral, dorso–ventral and medio–lateral axes12. Because HD is the most frequently observed polyglutamine disorder, analysis of an extensive collection of post-mortem brains has led to the development of a rating scale to grade neuropathological severity ranging from 0 to 4. Grade 0 brains show no macroscopic abnormality, but on microscopic examination reveal around 30% neuronal loss in the caudate nucleus. Similarly, it has been calculated from neuronal counts in post-mortem HD brains that neuronal loss probably begins early in life, and that at the time of onset of motor signs, about 30% of caudate neurons have already disappeared13,14,15. However, long-term clinical progression in HD is not strongly correlated with polyglutamine length, indicating that once underway, the worsening disease symptoms are heavily influenced by factors independent of the glutamine tract2,16. Similar studies in the rarer polyglutamine disorders, where different brain regions and neurons are targeted, have revealed differences in the effects of polyglutamine on progression and on symptomatology. The striking parallels, combined with obvious differences between the polyglutamine disorders, suggest that each disease is initiated by a novel deleterious property of the elongated glutamine tract, which produces neuronal death in a manner dictated by the activity, regulation, structure or localization of the host protein.

The above genotype–phenotype correlations lead to the formulation of five criteria for the mechanism that initiates pathogenesis: first, a threshold polyglutamine length below which the pathogenic mechanism is not triggered within the average human lifespan; second, progressiveness of the mechanism with increasing polyglutamine length; third, dominance of the mutant over the wild-type allele; fourth, a greater effect of polyglutamine length than allele dosage on the pathogenic mechanism; and last, cellular specificity that varies with protein context.

A novel property conferred by polyglutamine

The biochemical events that initiate pathogenesis in the polyglutamine disorders are not known, but these genetic criteria provide a means to assess the validity of candidate mechanisms. The polyglutamine segment seems to cause the mutant to adopt an unusual conformation. Evidence for this is found in the preferential reactivity of the mutant proteins with certain monoclonal antibodies and the disproportionate slowing of protein migration in SDS–PAGE. A property of the glutamine tract consistent with its fulfillment of the first four criteria is its capacity, when present in a short protein fragment, to promote self-aggregation, with a conversion to an insoluble β-sheet AMYLOID structure17,18. Such a property was predicted by Perutz19, and demonstrated experimentally using amino-terminal fragments representing 3–5% of huntingtin. In this circumstance, the glutamine tract is freed from constraints imposed by the remaining 3,000 amino acids of the protein. Indeed, it is likely that in the native protein, the propensity for insoluble conversion may give way to a potential for abnormal interactions with other cellular constituents. Similarly, the abnormal conformation of the glutamine tract could have an effect on the inherent activity of the host protein. Consequently, whereas pathogenesis is clearly triggered by the presence of the abnormal glutamine tract in each disorder, the disease pathway in each may begin differently, through an effect on the function of the host protein, through an effect on existing or new interactions of the full-length host protein, or through the process or consequences of forming insoluble polyglutamine amyloid. The selective patterns of cell death suggest that the initial effect may be on a different biochemical target in each disorder. However, once neuronal homeostasis has been disrupted, it is likely that many other downstream changes occur. These changes may be shared across diseases, may be polyglutamine-independent, and some of them lead to cell death.

Phenotypic model systems

The capacity to reproduce the genetic cause of a disorder in a model system is a relatively recent advance. Consequently, most data aimed at deciphering the mechanism of pathogenesis have come from attempts to reproduce aspects of the disease phenotype. Before isolation of the polyglutamine disease genes, chemicals were used to generate region-specific lesions in rodent and monkey brains, and to implicate particular pathways as potential participants in pathogenesis20. In particular, receptor-mediated glutamate excitotoxicity and deficits in oxidative metabolism have both attracted considerable interest. For example, the medium spiny neurons targeted in HD can be selectively ablated, in the presence of cortical glutamate input, by treatment with quinolinic acid, an agonist of the NMDA (N-methyl-d-aspartate) receptor. The same neurons can also be eliminated by systemic treatment with the mitochondrial toxins 3-nitropropionic acid and malonate. Overall, chemical lesion models have established that there are different ways to kill neurons and that not all neurons are equally susceptible to a given insult.

With the discovery that an expanded glutamine tract is involved in these disorders, an alternative strategy of generating phenotypes with gene-based lesions has emerged. Much literature has accumulated in the past three years describing the generation of mouse, lower organism and cell-culture models of the various disorders by overexpression of truncated or full-length mutant proteins from the polyglutamine disorders. The general finding has been that short fragments with expanded glutamine tracts readily form inclusions in vivo. Indeed, formation of morphological inclusions in a cell-culture model has also fulfilled the same four genetic criteria as aggregate formation in the test tube21. Inclusions do not efficiently kill cells, but cells expressing truncated fragments are more susceptible to apoptotic stimuli, indicating a clear homeostatic disruption22,23. Where cell death has been observed, it does not correlate well with inclusion formation23,24,25,26,27,28,29,30,31,32. The development of inclusions probably reflects the difficulty experienced by the cell in handling and turning over the mutant glutamine tract33,34. Indeed, these morphological structures contain not only mutant protein, but also ubiquitin, heat-shock proteins, PROTEASOME constituents and some interacting proteins35,36,37.

The first dramatic demonstration of the aggregation-promoting property of polyglutamine came from the generation of transgenic mice expressing exon 1 of the human HD gene with an extremely long CAG repeat22,38. Exon 1 encodes the first 89 amino acids of huntingtin (assuming a normal allele encoding 23 glutamines), corresponding to about 3% of the full protein. In these mice, the mutant glutamine tract is composed of around 150 residues. These mice show abnormal neurological phenotypes and severe diabetes, suffer brain shrinkage and die prematurely22,38,39. However, they do not show the massive striatal cell loss characteristic of HD. Instead, neurons throughout the brain and cells in the periphery develop large intranuclear inclusions. These inclusions are dynamic, as they can not only grow, but can also be eliminated by shutting off the continued production of the source fragment40. The observation of inclusions in the exon 1 model caused a re-examination of human HD pathology, which has revealed new pathological correlates of the disease: nuclear and cytoplasmic amino-terminal huntingtin inclusions in surviving cells41 and insoluble amyloid-like material in HD brain extracts18. Similar disease-protein aggregates have been detected in post-mortem brains from other polyglutamine disorders42. However, HD exon 1 mice reproduce only a subset of the human phenotypic spectrum, suggesting that the pathogenic mechanism is not affecting the same biochemical target as in human HD, that mice cannot show the massive neuronal cell loss seen in humans, or that different pathogenic processes in the mouse lead to premature death, superseding the HD pathogenic pathway.

Direct attempts to reproduce disease phenotype have used full-length mutant proteins. Disease models have been produced for SBMA, DRPLA, SCA1, SCA3 and HD, using cDNA transgenes43,44,45,46,47,48, usually driven by high-expression promoters with, in some cases, restricted expression patterns. For HD, an alternative model has been generated using a YEAST ARTIFICIAL CHROMOSOME (YAC) that contains a portion of chromosome 4p16.3, from which huntingtin expression is driven by the HD gene's own promoter49. Like the fragment models, the full-length protein models have also produced neuronal inclusions, albeit at lower frequency, and show various abnormal neurological phenotypes. However, the most striking feature of these models is overt neuronal cell death that shows selectivity in those models with a broad pattern of transgene expression46,48,49. These results suggest that the full-length disease protein confers specificity and neuronal toxicity that is not possessed by polyglutamine fragments alone. The cell death and other phenotypes observed in these models occur in much less time than it takes for disease manifestations to become apparent in humans. Whether this temporal difference results from more effective initiation of the same mechanism in the mouse, or from an effect on additional or different biochemical targets than in humans remains uncertain.

Mouse model systems for reproducing genotype

For two polyglutamine disorders — HD and SCA1 — homologous recombination has been used to introduce the human mutation into the corresponding mouse gene. These precise genetic models produce mutant protein from the endogenous locus, making them directly comparable with the human disease. The SCA1 knock-in mice express mutant protein at levels similar to wild-type animals50. Like transgenic mice that express mutant ataxin 1 at only double wild-type levels, the knock-in mice show none of the marked pathological changes characteristic of SCA1 transgenic mice with high-level targeted expression in Purkinje cells43. However, the SCA1 knock-in mice do show a subtle neurological phenotype.

HD knock-in models, which have been generated by three different groups, also express mutant protein at levels comparable with that observed in wild-type mice, but do not show the marked neurological phenotypes observed in transgenic animals expressing the full-length HD gene51,52,53. Subtle neurological abnormalities have been noted in two of the three models54,55, whereas none has been reported in the third51. However, a careful examination of huntingtin protein in the latter has revealed a molecular phenotype involving the mislocalization of a form of mutant huntingtin in the nucleus of striatal neurons56. This phenotype progresses over time towards the development of morphological inclusions and insoluble aggregate. The underlying mechanism for this molecular change fulfils all of the genetic criteria outlined above for the initiator of HD pathogenesis.

One possible explanation for the failure of the precise genetic models to produce the same devastating phenotypes that the mutations cause in humans is that, despite measurable differences in the behaviour of the mutant mouse protein that conform to the genetic criteria for pathogenesis initiation, the mouse does not possess a critical component needed to carry the disease pathway to its ultimate fruition. In the cDNA and YAC transgenic models of HD, overt neuronal death occurs, indicating that either the mutant human protein is capable of supporting both initiation and completion of the disease pathway in the mouse, or that this neuronal death results from a pathogenic mechanism distinct from that in humans. A more likely explanation for the lack of neuronal death in the knock-in models is that the lifespan of the mouse is simply not long enough to complete the full cascade of changes that follows the initiating event. This would be the case if the event that initiates pathogenesis (or its consequences) does not occur in a developmental stage-specific manner (that is, one mouse year equals several human decades) but rather in a time-dependent manner (that is, one year in the mouse equals one year in humans). For example, the longest HD allele ever reported, with about 250 CAG repeats, caused neurological abnormality only at 2.5 years of age with death following more than 13 years later57. Thus, the subtle changes detected in the knock-in models suggest that the mutant proteins result in early changes that progress only after a long period of time to the outright pathology characteristic of the human disorders. Consequently, they are potentially very valuable for investigating the pathogenic trigger (the mutant polyglutamine protein) and for identifying its initial biochemical target in each disorder, but cannot illuminate the final stages of cell death.

Prospects for developing rational treatment

The human and mouse studies of the polyglutamine disorders suggest a model of the disease process in any given neuron in which an abnormal conformation of the glutamine tract may interact with a specific biochemical target. This presumably sets off a cascade of changes that, after many years, kills the neuron. The cumulative effects of neuronal dysfunction and eventual death then determine the phenotypes manifested by the patient. From the therapeutic point of view, the pathological process can therefore be attacked at four levels (Fig. 2).

Figure 2: The pathogenic process in polyglutamine disorders.
figure2

The schematic shows the levels of the pathogenic process at which therapeutic intervention might be aimed or genetic modifiers may be sought, as they occur sequentially in time (left to right) in the susceptible neurons. Level I: The mutant polyglutamine protein (hand) with its expanded polyglutamine segment (red thumbnail), may be attacked with compounds that affect the abnormal conformation and might therefore be effective in preventing disease symptoms in all polyglutamine disorders. Level II: The primary biochemical target of the abnormal disease protein (blue button), is altered (red button) by the presence of mutant protein, so intervention may require disease-specific methods for reversing the alteration (for example, replacement of the target protein activity or preventing the interaction). Level III: The cascade of downstream events that results from the mutant protein–primary target interaction may occur sequentially in time and include events that contribute to the death of the susceptible neurons (red arrows) and events that cause changes in the neuron but are not essential for its ultimate demise (grey arrows). Therapeutics aimed at cell death and survival pathways, such as caspase inhibitors, growth factors and antioxidants, may be effective at Level III by blocking a subset of these events and their consequent symptoms. At level IV, the disease process has had its full impact and has destroyed susceptible cells. Consequently, the only option for therapy is neuron replacement.

The abnormal conformation of the expanded glutamine tract offers a pharmacological target with the potential for yielding broad-spectrum treatments to prevent initiation of the disease process in all polyglutamine disorders. It is not yet known whether the event that initiates pathogenesis involves a soluble form of the glutamine tract or one that has converted to an insoluble amyloid structure, so aggregation-inhibiting and promoting compounds are being sought. The in vitro aggregation property of polyglutamine has already been used as an assay to identify a handful of small molecules capable of inhibiting amyloid formation58,59. The screening of large drug libraries using in vitro, cell-based or lower-organism-based assays can be expected to produce further candidate aggregation inhibitors and promoters.

The biochemical partners initially affected by the abnormal polyglutamine conformation represent selective pharmacological targets for developing disease-specific preventative drugs. So far, none of the molecules that cooperate directly with the disease protein in triggering pathogenesis have been defined. However, the identification of the participants in the initiating step by genetic and biochemical means remains crucial to achieving a complete understanding of polyglutamine-mediated pathogenesis in these disorders.

Downstream from the initiating process, a myriad of biochemical changes can be expected. Some of these changes are crucial to producing the disease phenotype and some of them may be irrelevant to, or be minor players in, pathogenesis. The former alterations can also provide potential targets for therapeutic development, particularly when they involve pathways already known to participate in cell dysfunction or to promote cell survival in other systems. For example, the participation of CASPASES in apoptotic pathways and the handling of proteins by the ubiquitin–proteasome–chaperone system are two areas of particularly intensive investigation33,34,35,36,37,60,61,62,63,64,65,66. Therapeutics aimed at downstream pathways would not be aimed at the disease trigger, but instead be designed to mitigate the effects of the continuing disease process. Consequently, they may have limited capacity to block the full range of phenotypic effects of the disease genes, but could be very useful for slowing or halting the inexorable decline observed in polyglutamine disorders.

Finally, the replacement of lost tissue by neuronal transplantation is being explored in HD67. If successful, this approach might have applicability in other polyglutamine disorders. A new and exciting possibility is the production of new neurons in situ from neuronal precursors, a feat recently achieved in the mouse neocortex68.

Fortunately, distinct mouse models are already available to test potential therapies for their effect on both early and late events in pathogenesis. The interpretation of these findings, however, may not be clear until the treatments are also tested in people. For example, interventions such as the provision of an enriched environment, a DOMINANT-NEGATIVE caspase, creatine and MINOCYCLINE have all been reported to prolong survival of transgenic mice expressing exon 1 of the human HD gene by a few weeks69,70,71,72. As HD pathogenesis seems to be a time-dependent rather than a developmental process in both humans and mice, this might translate into a similar effect of only a few weeks in HD patients. However, as the HD exon 1 fragment in transgenic mice represents a rapidly lethal burden, even a small effect on this time course may translate into a comparable quantitative effect on the much more protracted time course of human HD.

Conclusion

Remarkable advances have been made during the past two decades in our knowledge of the neurodegenerative disorders, fuelled by genetic analysis in humans. These genetic findings have spawned a plethora of biochemical, cell-culture, lower-organism and mammalian model systems that are being used to investigate the pathogenic process. Moreover, the human studies have provided criteria for recognizing events involved in the initial pathogenic step. Much of the current analysis in model systems is aimed at exploring known biological pathways previously implicated in these and other neurological diseases. As demonstrated by the discovery of the polyglutamine disease genes, the power of genetic analysis is its capacity to identify that which was previously unknown and unsuspected. Consequently, a continued genetic approach may be required to identify the initiating events in the disease process while, at the same time, providing new targets for therapeutic development. Genetic analysis in model systems is a powerful approach that could reveal modifiers that enhance or suppress disease phenotypes. Evidence has already been obtained in yeast, fly and worm systems that certain molecular chaperones can inhibit polyglutamine aggregation, and these systems should prove valuable in uncovering other modifiers61,63,64,65,66,73,74,75,76. There is strong evidence for the existence of genetic modifiers in humans that can affect expression of the polyglutamine disorders11,77,78,79,80,81. Consequently, the further pursuit of genetic analysis in human patients is likely to reveal new and unsuspected approaches to treat these disorders.

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Acknowledgements

The authors thank J.-P. Vonsattel for his contribution. Their work is supported by the Huntington's Disease Society of America Coallition for the Cure, the Hereditary Disease Foundation and NIH.

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Glossary

SPINAL AND BULBAR MUSCULAR ATROPHY

Disorder characterized by progressive weakness and wasting of mouth, throat and skeletal muscles, which tends to affect only men.

POLYMORPHISM

The simultaneous existence in the same population of two or more forms (alleles) of a DNA sequence with a frequency that is greater than 1%.

MEDIUM SPINY NEURONS

Cell population that constitutes the main striatal inhibitory output to the globus pallidus.

SPINOCEREBELLAR ATAXIA

Disorder characterized by progressive cerebellar atrophy, which leads to gait ataxia and incoordination.

CHOREOATHETOSIS

Movement disorder characterized by constant writhing and jerking motion.

SDS–PAGE

Sodium dodecyl sulphate-polyacrylamide gel electrophoresis. A method for resolving a multimeric protein into its subunits and determining their separate molecular weights.

AMYLOID FIBRES

Insoluble, relatively inert fibres that are resistant to proteolysis, made from proteins in a β-pleated structure.

PROTEASOME

Protein complex responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.

YEAST ARTIFICIAL CHROMOSOME

A cloning vector capable of propagation in yeast, where it functions as an artificial chromosome.

CASPASES

Cysteine proteases involved in apoptosis, which cleave at specific aspartate residues.

DOMINANT-NEGATIVE

A mutant protein that reduces the activity of the wild-type form.

MINOCYCLINE

An antibiotic that belongs to the tetracycline group.

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Gusella, J., MacDonald, M. Molecular genetics: Unmasking polyglutamine triggers in neurodegenerative disease. Nat Rev Neurosci 1, 109–115 (2000). https://doi.org/10.1038/35039051

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