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Toward understanding Machado-Joseph disease
Maria do Carmo Costa1, Henry L Paulson
1Department of Neurology, University of Michigan, A. Alfred Taubman Biomedical Sciences Research Building-BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA. mariadoc@med.umich.edu
Progress in Neurobiology
|December 3, 2011
Summary
Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3, involves a toxic expansion in the ATXN3 protein. Understanding ATXN3 dysfunction is key to developing therapies for this neurodegenerative disorder.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is a common inherited neurodegenerative disorder.
- It is characterized by a CAG repeat expansion in the ATXN3 gene, leading to an abnormal polyglutamine (polyQ) tract in the ATXN3 protein.
Purpose of the Study:
- This review focuses on the function and dysfunction of the ATXN3 protein in MJD.
- It also highlights recent advances in potential therapeutic strategies for MJD.
Main Methods:
- The review synthesizes current knowledge on ATXN3's role as a deubiquitinating enzyme (DUB) and its involvement in proteostasis.
- It discusses findings from various cellular and animal models of MJD to understand ATXN3 dysfunction.
Main Results:
- ATXN3's normal function involves regulating protein stability and activity in pathways related to proteotoxic stress, aging, and cell differentiation.
- PolyQ expansion in ATXN3 alters its conformation, leading to impaired interactions and the formation of insoluble aggregates.
Conclusions:
- While significant progress has been made, the precise molecular mechanisms of ATXN3-induced neurotoxicity in MJD remain unclear.
- Further understanding of these complex mechanisms is crucial for developing effective treatments for this fatal disease.
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