Progress in Neurobiology

Department of Neurology, University of Michigan, A. Alfred Taubman Biomedical Sciences Research Building-BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
Progress in Neurobiology (Impact Factor: 9.99). 11/2011; 97(2):239-57. DOI: 10.1016/j.pneurobio.2011.11.006
Source: PubMed


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.

Download full-text


Available from: Maria do Carmo Costa, Oct 04, 2015
56 Reads
  • Source
    • "RESULTS AND DISCUSSION GFP Reports Internal Retinal Degeneration Caused by a polyQ Protein Spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease) is considered to be the most common autosomal dominantly inherited ataxia and is one of at least 10 polyQ-related neurodegenerative diseases that include Huntington's disease and several SCAs (Todi et al., 2007; Williams and Paulson, 2008). SCA3 is an age-dependent disease that is caused by abnormal expansion in the polyQ tract of the deubiquitinating enzyme ataxin-3 (Costa Mdo and Paulson, 2012). This was one of the first neurodegenerative diseases to be modeled in vivo using the fruit fly in work done by the Bonini laboratory, where two different models were generated: 1) a truncated version of ataxin-3 that comprises the isolated 78-amino-acid polyQ stretch (Warrick et al., 1998) and 2) a full-length version of the human pathogenic ataxin-3 protein with 84 polyQ (Warrick et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Age-related neurodegeneration has been studied extensively through the use of model organisms, including the genetically versatile Drosophila melanogaster. Various neurotoxic proteins have been expressed in fly eyes to approximate degeneration occurring in humans, and much has been learned from this heterologous system. Although Drosophila expedites scientific research through rapid generational times and relative inexpensiveness, one factor that can hinder analyses is the examination of milder forms of degeneration caused by some toxic proteins in fly eyes. Whereas several disease proteins cause massive degeneration that is easily observed by examining the external structure of the fly eye, others cause mild degeneration that is difficult to observe externally and requires laborious histological preparation to assess and monitor. Here, we describe a sensitive fluorescence-based method to observe, monitor, and quantify mild Drosophila eye degeneration caused by various proteins, including the polyglutamine disease proteins ataxin-3 (spinocerebellar ataxia type 3) and huntingtin (Huntington's disease), mutant α-synuclein (Parkinson's disease), and Aβ42 (Alzheimer's disease). We show that membrane-targeted green fluorescent protein reports degeneration robustly and quantitatively. This simple yet powerful technique, which is amenable to large-scale screens, can help accelerate studies to understand age-related degeneration and to find factors that suppress it for therapeutic purposes. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 09/2014; 92(9). DOI:10.1002/jnr.23395 · 2.59 Impact Factor
  • Source
    • "Based on in vitro biochemistry, cell-based studies and in vivo work in mice, C. elegans and Drosophila, ataxin-3 seems to function in the UPP (Matos et al., 2011; Costa Mdo and Paulson, 2012). Under some circumstances, ataxin-3 may enhance the degradation of some proteasome substrates (e.g., in Endoplasmic Reticulum (ER)-Associated Degradation, Wang et al., 2006, and in relation with the Ub ligase CHIP, Scaglione et al., 2011), while under other conditions it may decelerate proteasomal degradation of other proteins (Zhong and Pittman, 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Ubiquitin-Proteasome Pathway (UPP), which is critical for normal function in the nervous system and is implicated in various neurological diseases, requires the small modifier protein ubiquitin to accomplish its duty of selectively degrading short-lived, abnormal or misfolded proteins. Over the past decade, a large class of proteases collectively known as deubiquitinating enzymes (DUBs) has increasingly gained attention in all manners related to ubiquitin. By cleaving ubiquitin from another protein, DUBs ensure that the UPP functions properly. DUBs accomplish this task by processing newly translated ubiquitin so that it can be used for conjugation to substrate proteins, by regulating the “where, when, and why” of UPP substrate ubiquitination and subsequent degradation, and by recycling ubiquitin for re-use by the UPP. Because of the reliance of the UPP on DUB activities, it is not surprising that these proteases play important roles in the normal activities of the nervous system and in neurodegenerative diseases. In this review, we summarize recent advances in understanding the functions of DUBs in the nervous system. We focus on their role in the UPP, and make the argument that understanding the UPP from the perspective of DUBs can yield new insight into diseases that result from anomalous intra-cellular processes or inter-cellular networks. Lastly, we discuss the relevance of DUBs as therapeutic options for disorders of the nervous system.
    Frontiers in Molecular Neuroscience 08/2014; 7:1. DOI:10.3389/fnmol.2014.00072 · 4.08 Impact Factor
  • Source
    • "MJD is more prevalent in populations with Portuguese Azorean ancestry (Gaspar et al., 2001; Castilhos et al., 2013). The extended polyglutamine tract in the mutant protein induces neuronal intranuclear inclusions (NII) and neurodegeneration (Costa and Paulson, 2012). Symptoms generally appear later in life (mean age of 32-40 years) and mainly affect postural balance and the coordination of gait, speech and fine movements of the hands; patients are often confined to wheelchairs and, later, become bedridden (Sequeiros and Coutinho, 1993; Jardim et al., 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Machado-Joseph disease (MJD) is an autosomal dominant, late-onset neurological disorder and the most common form of spinocerebellar ataxia (SCA) worldwide. Diagnostic genetic testing is available to detect the disease-causing mutation by direct sizing of the CAG repeat tract in the ataxin 3 gene. Presymptomatic testing (PST) can be used to identify persons at risk of developing the disease. Genetic counseling provides patients with information about the disease, genetic risks, PST, and the decision-making process. In this study, we present the protocol used in PST for MJD and the relevant observations from two centers: Brazil (Porto Alegre) and Portugal (Porto). We provide a case report that illustrates the significant ethical and psychological issues related to PST in late-onset neurological disorders. In both centers, counseling and PST are performed by a multidisciplinary team, and genetic testing is conducted at the same institutions. From 1999 to 2012, 343 individuals sought PST in Porto Alegre; 263 (77%) of these individuals were from families with MJD. In Porto, 1,530 individuals sought PST between 1996 and 2013, but only 66 (4%) individuals were from families with MJD. In Brazil, approximately 50% of the people seeking PST eventually took the test and received their results, whereas 77% took the test in Portugal. In this case report, we highlight several issues that might be raised by the consultand and how the team can extract significant information. Literature about PST testing for MJD and other SCAs is scarce, and we hope this report will encourage similar studies and enable the implementation of PST protocols in other populations, mainly in Latin America.
    Genetics and Molecular Biology 03/2014; 37(1 Suppl):263-70. DOI:10.1590/S1415-47572014000200012 · 1.20 Impact Factor
Show more