Regulation of BACE1 by miR-29a/b in a cellular model of Spinocerebellar Ataxia 17.

Polyglutamine diseases are a class of neurodegenerative disorders characterized by expansion of polyglutamine repeats, protein aggregation and neuronal cell death in specific regions of the brain. The expansion of a polyglutamine repeat in the TATA binding protein (TBP) causes a neurodegenerative disease, Spinocerebellar Ataxia 17 (SCA17). This disease is characterized by intranuclear protein aggregates and selective loss of cerebellar neurons, including Purkinje cells. MicroRNAs are small, endogenous, regulatory non-coding RNA molecules that bind to messenger RNAs with partial complementarity and interfere in their expression. Here, we used a cellular model of SCA17 where we expressed TBP with 16 (normal) or 59 (pathogenic) polyglutamines and found differential expression of several microRNAs. Specifically, we found two microRNAs, miR-29a/b, were down-regulated. With miR-29a/b down regulation, we found an increased expression of targets of miR-29a/b -beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), p53 upregulated modulator of apoptosis (PUMA) and BAK, increased cytochrome c release and apoptosis. Restoration of miR-29a/b in the pathogenic polyglutamine background reduced the BACE1expression. While, antagomiRs against miR-29a/b resulted in an increase in BACE1 levels and neuronal apoptosis. In spite of the elevation of BACE1 in Alzhemiers disease, its role in neuronal cell death has not been established. Here, we show that increased BACE1 expression is not sufficient to cause apoptosis. However restoring level of BACE1 to normal in polyglutamine cells partially reduced neuronal apoptosis. We show a role for the miR-29a/b-BACE1 regulatory interaction in SCA17, suggesting that this microRNA could be part of a common molecular mechanism leading to neuronal cell death in multiple neurodegenerative disorders. The identification of a common mechanism of microRNA mediated neurodegeneration not only improves our understanding of the process, but also provides promising and novel therapeutic targets.