Over-expression of inducible HSP70 chaperone suppresses neuropathology andimproves motor function in SCA1 mice

Many neurodegenerative diseases are caused by gain-of-function mechanisms i n which the disease-causing protein is altered, becomes toxic to the cell, and aggregates. Among these 'proteinopathies' are Alzheimer's and Parkinson 's disease, prion disorders and polyglutamine diseases. Members of this lat ter group, also known as triplet repeat diseases, are caused by the expansi on of unstable CAG repeats coding for glutamine within the respective prote ins. Spinocerebellar ataxia type 1 (SCA1) is one such disease, characterize d by loss of motor coordination due to the degeneration of cerebellar Purki nje cells and brain stem neurons. In SCA1 and several other polyglutamine d iseases, the expanded protein aggregates into nuclear inclusions (NIs). Bec ause these NIs accumulate molecular chaperones, ubiquitin and proteasomal s ubunits-all components of the cellular protein re-folding and degradation m achinery-we hypothesized that protein misfolding and impaired protein clear ance might underlie the pathogenesis of polyglutamine diseases. Over-expres sing specific chaperones reduces protein aggregation in transfected cells a nd suppresses neurodegeneration in invertebrate animal models of polyglutam ine disorders. To determine whether enhancing chaperone activity could miti gate the phenotype in a mammalian model, we crossbred SCA1 mice with mice o ver-expressing a molecular chaperone (inducible HSP70 or iHSP70). We found that high levels of HSP70 did indeed afford protection against neurodegener ation.