Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD) is the most common form of spinocerebellar ataxia in the world. The main clinical hallmark of SCA3 is a dysfunction of motor coordination that can affect gaze, speech, gait and balance. SCA3 is caused by an abnormal expansion in the axtaxin-3 protein, called a polyglutamine (polyQ) repeat, which causes the ataix-3 protein to clump together into aggregates. Ataxin-3 is expressed in most human tissues and has a role in maintaining protein homeostasis (proteostasis). If protein homeostasis declines, misfolded proteins begin to accumulate and aggregate in the cell, which can disrupt normal cellular functions and even cause cell death. Protein degradation is a key mechanism to avoid accumulation of misfolded and damaged proteins. The two main protein degradation systems in the cell are the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathways. Evidence suggests axatin-3 aggregates impair both protein degradation systems which contributes to disease pathology. However, researchers do not yet know exactly why the protein degradation systems fail and how the body responds across tissues to compensate for this failure. Understanding the interplay of proteasome activity and autophagy in SCA3 (and other polyQ disorders) could identify novel targets for therapeutic intervention.
|Effective start/end date||7/1/20 → 6/30/21|
- National Ataxia Foundation (Letter 3/3/20)