University of California, San Francisco (UCSF)

Longitudinal Analysis to Study PolyQ-dependent Death Mechanisms in Specific Neuronal Subpopulations

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Huntington’s disease (HD) is a fatal, incurable autosomal inherited neurodegenerative disorder caused by a mutation that increases the number of polyglutamines in huntingtin protein (htt). Mutant htt is expressed ubiquitously, but clinical symptoms are attributed to selective death of specific neurons in the brain, mainly in the striatum. The molecular mechanisms by which mutant htt leads to specific neuronal death are not known. Mutant htt forms inclusion bodies (IBs) and they constitute a pathological hallmark of HD. We developed an automated microscope to follow the same population of neurons over long periods. We simultaneously monitored changes in factors in which we were interested to determine whether they predicted a particular biological outcome, such as neuronal longevity. We found that IB formation improved neuronal survival and that the levels of diffuse forms of mutant htt predicted neuronal death. Using antibodies to characterize different species of diffuse forms of mutant htt and survival analysis, we found that a monomeric form of mutant htt was one of the most toxic species. Finally, we found that the risk of IB formation is higher in cortical than striatal neurons. Therefore, IB formation may be one mechanism determining the survival of specific neuronal subpopulations in HD.