Machado-Joseph disease/spinocerebellar ataxia type 3

Abstract

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), may be the most common dominantly inherited ataxia in the world. Here I will review historical, clinical, neuropathological, genetic, and pathogenic features of MJD, and finish with a brief discussion of present, and possible future, treatment for this currently incurable disorder. Like many other dominantly inherited ataxias, MJD/SCA3 shows remarkable clinical heterogeneity, reflecting the underlying genetic defect: an unstable CAG trinucleotide repeat that varies in size among affected persons. This pathogenic repeat in MJD/SCA3 encodes an expanded tract of the amino acid glutamine in the disease protein, which is known as ataxin-3. MJD/SCA3 is one of nine identified polyglutamine neurodegenerative diseases which share features of pathogenesis centered on protein misfolding and accumulation. The specific properties of MJD/SCA3 and its disease protein are discussed in light of what is known about the entire class of polyglutamine diseases.

Figure 1. Ataxin-3 and related Josephin domain proteins

Ataxin-3 is a relatively small protein with a glutamine repeat near the carboxyl terminus. The approximate ranges for normal and disease repeats are shown. The N-terminal conserved “josephin” catalytic domain, a predicted coiled-coil domain and several ubiquitin interacting motifs (UIMs) are also shown. Ataxin-3 is one member of the small Josephin DUB family, two other members of which are josephin-1 and josephin-2, encoded by different genes. All three proteins share the catalytic amino acid triad (C, H, and D/N) and function as DUBs.