Rinsho Shinkeigaku (Clinical Neurology)

The 49th Annual Meeting of the Japanese Society of Neurology

Pathomechanism of polyglutamine diseases and strategic design for their therapies

Nobuyuki Nukina, M.D.

Laboratory for Structural Neuropathology, RIKEN Brain Science Institute

The pathomechanism of neurodegenerative disorders are not fully elucidated yet. In Huntington Disease (HD) and some hereditary spinocerebellar ataxias, expanded polyglutamine (polyQ) accumulates and forms aggregates in neuronal nuclei. We have been studying the pathological process by which the mutation induces the misfolding and accumulation of the gene product leading to neuronal degeneration using cell biological and structural biological approaches. We analyzed the pathological process in polyQ disease cellular model and the structural changes of polyQ-induced protein misfolding using our polyQ-bearing myoglobin model system. Using these models, we found that expanded polyQ forms a beta-sheet structure and causes proteasome inhibition. We further analyzed the structural basis of toxic aggregates, which suggested the polyglutamine exposed form may be more toxic to sequester several important functional molecules. We also established the method for analyzing aggregate interacting proteins (AIPs) and reported several AIPs including transcription factor NF-Y.
Based on the pathomechanism, which we revealed, we developed several experimental therapies, including stabilizing abnormal protein, activating proteasomal function and enhancing the selective degradation of abnormal protein through chaperone-mediated autophagy.
Full Text of this Article in Japanese PDF (163K)

(CLINICA NEUROL, 48: 913|914, 2008)
key words: polyglutamine diseases, beta sheet, aggregate, chaperone-mediated autophagy

(Received: 16-May-08)