Thesis

Activation of puromycin-sensitive aminopeptidase to enhance in the degradation of aggregate prone proteins

Pathological aggregation of specific proteins underlies many neurological disorders including Tauopathies, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and spinocerebellar ataxia type-3. Recent research has identified puromycin sensitive aminopeptidase (PSA; NPEPPS) as a potential target in the treatment of tauopathies, as overexpression of PSA reduces total tau levels both in vitro and in vivo, while PSA overexpression does not cause abnormalities in either mouse or fly. PSA may also be involved in the degradation of several other pathologically aggregating proteins. The inhibition of PSA has led to increased aggregation of ataxin-3, huntingtin, SOD1, and -synuclein, which are the major components of the protein aggregates found in spinocerebellar ataxia type-3, Huntington's disease, amyotrophic lateral sclerosis, and Parkinson's disease, respectively. This suggests that PSA may be a key therapeutic target for a number of neurological diseases characterized by protein aggregation beyond tauopathies. In this study, we test the effects of various compounds, previously identified as enhancers of PSA activity, on the degradation of endogenous forms of these aggregate prone proteins at non-toxic concentrations in primary neuronal cultures. We demonstrate that the activation of PSA through the addition of these compounds lowers endogenous huntingtin and SOD1 levels in primary mouse cortical culture, as well as endogenous huntingtin, SOD1, ataxin-3, and -synuclein levels in primary human neural progenitor cells while not causing detectable harm to the cells. This suggests that the compounds tested may be a promising prospect for additional drug development in the treatment of a range of neurodegenerative diseases.

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