Parkin and its association with alpha-synuclein and AbetaPP in inclusion-body myositis and AbetaPP-overexpressing cultured human muscle fibers.

UNLABELLED

Parkin, an E3-ubiquitin ligase in the ubiquitin-proteasome system, facilitates degradation of alpha-synuclein and other proteins. Since ubiquitinated multiprotein-aggregates containing amyloid-beta (Abeta), alpha-synuclein, and other proteins, are characteristic of sporadic inclusion-body myositis (s-IBM) muscle fibers, we asked whether parkin might have a role in s-IBM pathogenesis. We studied the association of parkin with alpha-synuclein and Abeta-precursor protein (AbetaPP) in s-IBM muscle biopsies and in our IBM model based on overexpression of AbetaPP into cultured human muscle fibers. We report the following in s-IBM muscle fibers: a) parkin was increased 2.7 fold and accumulated in aggregates also containing Abeta and alpha-synuclein; b) alpha-synuclein was increased 6.3 fold; c) parkin physically associated with alpha-synuclein and AbetaPP; d) alpha-synuclein and AbetaPP were ubiquitinated. In the IBM model: a) parkin was increased 2.7 fold, b) it associated with alpha-synuclein and AbetaPP.

CONCLUSION

1. This is the first demonstration that in a human muscle disease alpha-synuclein associates with parkin, and might be ubiquitinated by it. 2. The small increase of parkin relative to the much larger increase of alpha-synuclein might be insufficient to secure complete ubiquitination and consequent degradation of alpha-syn. 3. AbetaPP might be a novel substrate of parkin.