The heat shock protein 70 co-chaperone ST13 - a candidate disease-modifying gene for Parkinson disease

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Parkinson’s disease (PD) is a neurodegenerative illness that affects five million people worldwide. In both idiopathic (sporadic) PD and familial PD caused by α-synuclein (SNCA) mutations, the pathologic hallmarks of the disease are large fibrillar α-synuclein-protein (αS) deposits (so called Lewy bodies) and degeneration of dopaminergic neurons in the substantia nigra. SNCA toxicity in cellular, yeast, and fly models of PD can be suppressed by a molecular chaperone, heat shock protein 70 (HSP70). Recently, my host laboratory found that in the substantia nigra of patients with PD, expression of HSP70 members is highly perturbed. Importantly, significant lower levels of the HSP70 co-chaperone ST13 were detected in blood of PD patients. Thus, we hypothesize that in common, sporadic PD reduced ST13 chaperone activity exacerbates αS aggregation and toxicity.I outline a research plan to (i) determine whether the co-chaperone ST13 suppresses α-synuclein aggregation and toxicity in cultured dopaminergic cells. (ii) I will precisely delineate changes in ST13 mRNA and protein expression in vulnerable dopaminergic neurons of the substantia nigra and in peripheral blood specimens of PD patients using kinetic, quantitative PCR, quantitative Western blotting, and immunohistochemistry. These studies will provide powerful new insights into the involvement of chaperones in the pathobiology of human PD.