Toward understanding Machado–Joseph disease

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Abstract

Machado–Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is the most common inherited spinocerebellar ataxia and one of many polyglutamine neurodegenerative diseases. In MJD, a CAG repeat expansion encodes an abnormally long polyglutamine (polyQ) tract in the disease protein, ATXN3. Here we review MJD, focusing primarily on the function and dysfunction of ATXN3 and on advances toward potential therapies. ATXN3 is a deubiquitinating enzyme (DUB) whose highly specialized properties suggest that it participates in ubiquitin-dependent proteostasis. By virtue of its interactions with VCP, various ubiquitin ligases and other ubiquitin-linked proteins, ATXN3 may help regulate the stability or activity of many proteins in diverse cellular pathways implicated in proteotoxic stress response, aging, and cell differentiation. Expansion of the polyQ tract in ATXN3 is thought to promote an altered conformation in the protein, leading to changes in interactions with native partners and to the formation of insoluble aggregates. The development of a wide range of cellular and animal models of MJD has been crucial to the emerging understanding of ATXN3 dysfunction upon polyQ expansion. Despite many advances, however, the principal molecular mechanisms by which mutant ATXN3 elicits neurotoxicity remain elusive. In a chronic degenerative disease like MJD, it is conceivable that mutant ATXN3 triggers multiple, interconnected pathogenic cascades that precipitate cellular dysfunction and eventual cell death. A better understanding of these complex molecular mechanisms will be important as scientists and clinicians begin to focus on developing effective therapies for this incurable, fatal disorder.

Highlights

► MJD is a neurodegenerative disease caused by polyQ expansion in ATXN3. ► ATXN3 is a deubiquitinating enzyme participating in ubiquitin-mediated proteostasis. ► PolyQ expansion in ATXN3 triggers cellular dysfunction and selective neuronal death. ► Improved understanding of disease mechanisms is suggesting routes to therapy.

Introduction

Many hereditary neurodegenerative diseases manifest later in life and are characterized by the progressive and selective loss of neuronal cell bodies, axons, dendrites and/or synapses. For decades scientists have sought to clinically define specific neurodegenerative diseases and their genetic causes in order to achieve a molecular diagnosis, offer presymptomatic and prenatal testing to affected families, generate cellular and animal models toward understanding pathogenic mechanisms and facilitate the development of potential therapies. Studies over the past 20 years have established that an unusual type of mutation, dynamic repeat expansions, cause many inherited neurodegenerative diseases.

Among the dynamic repeat expansion diseases, the polyglutamine (polyQ) disorders caused by CAG repeat expansions represent the most common class, although each polyglutamine disease is relatively rare. In all polyQ diseases the CAG repeat expansion is translated into an abnormally long stretch of glutamine residues in the corresponding disease protein. Spinal bulbar muscular atrophy (SBMA) was the first discovered polyQ disease, identified 20 years ago (La Spada et al., 1991). Since then nine additional polyQ diseases have been identified: the spinocerebellar ataxias (SCA) types 1, 2, 3 (also known as Machado–Joseph disease), 6, 7 and 17, dentatorubral-pallidoluysian atrophy (DRPLA), Huntington disease (HD), and, most recently, Huntington disease-like 2 (HDL2). All polyQ diseases are dominantly inherited disorders except SBMA, which is X-linked. The current review focuses on MJD/SCA3 and its disease protein, ataxin-3 (ATXN3).

Development of rational, targeted therapies for these diseases will be facilitated by knowing the pathogenic mechanism of the disease-causing mutation. As a class, polyQ diseases share certain features that suggest a general toxic mechanism triggered by expanded polyQ, which might be targetable in class-wide therapeutics. All 10 polyglutamine diseases are characterized by selective neurodegeneration in the central nervous system (CNS) despite widespread expression of the disease proteins. Indeed there is little correlation between the expression pattern of polyQ proteins and the sites of CNS pathology. The disease proteins are widely expressed throughout the CNS with two notable exceptions: the CACNA1A calcium channel subunit in SCA6, which is mainly expressed in affected cerebellar Purkinje cells, and the androgen receptor in SBMA, which is primarily expressed in vulnerable motor neurons. Another shared feature of polyQ disease proteins is their propensity to misfold, oligomerize, and form intracellular aggregates and inclusions that constitute a pathological disease hallmark. The misfolding and aggregation of polyQ disease proteins have been targets of some proposed therapeutic strategies (Bauer and Nukina, 2009, Di Prospero and Fischbeck, 2005, Matos et al., 2011, Williams and Paulson, 2008).

Despite these shared features, however, each polyQ disease is a distinctive disorder with characteristic symptomatology and pathology occurring in specific brain regions. PolyQ disease proteins differ in size, cellular localization and biological function, suggesting that the toxic effect of a given polyQ expansion depends on the specific protein context and that the particular details of pathogenesis may be unique to each disease.

Here we review Machado–Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), focusing primarily on the molecular properties of the disease protein, ATXN3, both in normal and pathogenic contexts, and on recent progress toward therapeutic development for this fatal disorder.

Section snippets

Clinical features

The discovery of MJD (OMIM#109150) illustrates the difficulty of defining a disease as a single entity when variable symptoms themselves represent a hallmark of the disease. MJD was first described in Northern American families of Azorean ancestry. Between 1972 and 1977 the disease was identified in four families, reported as four distinct entities named “Machado disease” (Nakano et al., 1972), “nigro-spino-dentatal degeneration” (Woods and Schaumburg, 1972), “Joseph disease” (Rosenberg et al.,

Genetics of MJD

From its initial description in 1972, MJD was recognized to be a dominantly inherited genetic disorder. Eleven years later, the MJD disease gene was mapped to chromosome 14q32.1 (Takiyama et al., 1993). That same year, the presence of clinical features of ataxia apparently distinct from MJD in some French families that did not map to the SCA1 or SCA2 loci led researchers to propose the existence of a novel, dominantly inherited ataxia which they named spinocerebellar ataxia type 3 (SCA3) (

The ATXN3 product, ATXN3

An evolutionarily conserved protein, ATXN3 has a long list of orthologs in a wide range of species (Costa et al., 2004, Linhartova et al., 1999, Rodrigues et al., 2007, Schmitt et al., 1997). Normal (i.e. nonexpanded) human ATXN3 has a molecular weight of approximately 42 kDa, varying slightly in size depending on the length of the polymorphic glutamine repeat. Defining the function, localization, stability and physiological role of wild-type ATXN3 is critically important if scientists want to

Mutant ATXN3 and disease pathogenesis

Expansion of the polyQ track likely induces a conformational change in ATXN3 that affects many properties of the protein: stability and degradation, subcellular localization, molecular interactions with other proteins, and propensity to aggregate. These altered properties result in loss and/or gain of function, leading to cellular dysfunction and selective neuronal cell death.

Development of MJD therapeutics

MJD and the other polyQ diseases are currently untreatable. Despite the absence of preventive treatment, many symptoms of disease can be treated using pharmacological and nonpharmacological measures. Details about symptomatic therapy and clinical trials in MJD can be found in several recent reviews (Bettencourt and Lima, 2011, Paulson, 1998]).

Seeking a preventive therapy, MJD researchers have explored pharmacological and genetic approaches, both of which have shown some promise. As described

Final remarks

This year marks the 20th anniversary of an historical moment in human genetics: the discovery that heritable human diseases can be caused by dynamic repeat mutations. In 1991, expanded CCG and CAG repeat sequences were reported as the molecular basis of Fragile X syndrome and SBMA, respectively (Kremer et al., 1991, La Spada et al., 1991). Soon afterward, expansion of polyQ-encoding CAG repeats was revealed to be the cause of the largest class of dynamic repeat disorders, the polyQ

Acknowledgements

We would like to thank Drs. Sokol V. Todi and K. Mathew Scaglione for critical reading of the manuscript. MCC is the recipient of fellowships from Fundação para a Ciência e a Tecnologia (FCT) (SFRH/BPD/28560/2006) and National Ataxia Foundation (NAF Research Fellowship Award 2011). HLP is funded by NIH NS038712, the Mateus family fund, and the Ataxia Medical Research Foundation.

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