Progress in pathogenesis studies of spinocerebellar ataxia type 1

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited disorder cha racterized by progressive loss of coordination, motor impairment and the de generation of cerebellar Purkinje cells, spinocerebellar tracts and brainst em nuclei. Many dominantly inherited neurodegenerative diseases share the m utational basis of SCA1: the expansion of a translated CAG repeat coding fo r glutamine. Mice lacking ataxin-1 display learning deficits and altered hi ppocampal synaptic plasticity but none of the abnormalities seen in human S CA1; mice expressing atasin-1 with an expanded CAG tract (82 glutamine resi dues), however, develop Purkinje cell pathology and ataxia. These results s uggest that mutant atasin-1 gains a novel function that leads to neuronal d egeneration. This novel function might involve aberrant interaction(s) with cell-specific protein(s), which in turn might explain the selective neuron al pathology. Mutant ataxin-1 interacts preferentially with a leucine-rich acidic nuclear protein that is abundantly expressed in cerebellar Purkinje cells and other brain regions affected in SCA1. Immunolocalization studies in affected neurons of patients and SCA1 transgenic mice showed that mutant ataxin-1 localizes to a single, ubiquitin-positive nuclear inclusion (NI) that alters the distribution of the proteasome and certain chaperones. Furt her analysis of NIs in transfected HeLa cells established that the proteaso me and chaperone proteins co-localize with ataxin-1 aggregates, Moreover, o verexpression of the chaperone HDJ-2/HSDJ in HeLa cells decreased ataxin-1 aggregation, suggesting that protein misfolding might underlie NI formation . To assess the importance of the nuclear localization of ataxin-1 and its role in SCA1 pathogenesis, two lines of transgenic mice were generated. In the first line, the nuclear localization signal was mutated so that full-le ngth mutant ataxin-1 would remain in the cytoplasm; mice from this line did not develop an ataxia or pathology. This suggests that mutant ataxin-1 is pathogenic only in the nucleus. To assess the role of the aggregates, trans genic mice were generated with mutant ataxin-1 without the self-association domain (SAD) essential for aggregate formation. These mice developed ataxi a and Purkinje cell abnormalities similar to those seen in SCA1 transgenic mice carrying full-length mutant ataxin-1, but lacked NIs. The nuclear mili eu is thus a critical factor in SCA1 pathogenesis, but large NIs are not ne eded to initiate pathogenesis. They might instead be downstream of the prim ary pathogenic steps. Given the accumulated evidence, we propose the follow ing model for SCA1 pathogenesis: expansion of the polyglutamine tract alter s the conformation of ataxin-1, causing it to misfold. This in turn leads t o aberrant protein interactions. Cell specificity is determined by the cell -specific proteins interacting with atasin-1. Submicroscopic protein aggreg ation might occur because of protein misfolding, and those aggregates becom e detectable as NIs as the disease advances. Proteasome redistribution to t he NI might contribute to disease progression by disturbing proteolysis and subsequent vital cellular functions.