Dynein mutations impair autophagic clearance of aggregate-prone proteins

Speaker：黃淑真                              Time：13:10~14:00; 2006/03/29

Commentator：蔣輯武老師             Room : 601

Abstract：

Dyneins are minus end-directed microtubule motors that move cargo from the distal ends of axons toward neuronal cell bodies. Mutant genes that regulate dynein motor machinery result in motor neuron disease such as amyotrophic lateral sclerosis (ALS), Parkinson disease, and Hungtington disease¹. The reasons for aggregates or inclusions formation in human motor neuron disease are unknown. Previous study showed that the formation of different aggregate-prone proteins is strongly dependent on autophagy. Here the authors hypothesize that aggregates formation result from failed clearance of aggregate-prone proteins that cause varied motor neuron disease, such as mutant proteins with polyglutamine expansions that cause Huntington disease and mutant α-synucleins (A53T and A30P) that cause familial Parkinson disease². They demonstrated that chemical inhibition of dynein function impairs clearance of mutant aggregate-prone proteins. They also showed that dominant-negative inhibition of dynein interferes with clearance of aggregate-prone protein. Moreover, inhibition of dynein function impairs autophagosome-lysome fusion. Furthermore, they found that reducing kinesin function enhanced toxicity of mutant huntingtin, but the effects of dynein mutations on huntingtin toxicity were ambigious. Finally, they demonstrated that dynein dysfunction enhanced the phenotype in a mouse model of Huntington disease. They provided a new mechanim of inclusion formation involved in dynein mutation and related with motor neuron disease.³

References:

1.      Hafezparast, M. et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300, 808–812 (2003).

2.      Ravikumar, B., Duden, R. & Rubinsztein, D.C. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11, 1107–1117 (2002).

3.      Brinda Ravikumar et al. Dynein mutations impair autophagic clearance of aggregate-prone protein. Nature Genetics 37, 771 - 776 (2005).