Parkinson disease (PD) is a common neurodegenerative movement disorder characterized by an extensive and progressive loss of dopaminergic neurons in the substantia nigra pars compacta. An emergent dogma applicable to PD and other neurodegenerative diseases is that neuronal dysfunction and death are mediated by protein aggregates, commonly known as 'oligomers'. Central to the pathophysiology of PD is a-synuclein (aSyn), an abundant presynaptic protein of unknown function. In both familial and 'sporadic' PD, aggregated aSyn deposits into intracellular fibrillar inclusions called Lewy bodies and Lewy neurites. Aggregated aSyn leads to an impairment of the ubiquitin-proteasome system resulting in accumulation of aSyn in model systems. The 'molecular chaperones' are a natural defense against protein misfolding and aggregation. Two molecular chaperones of the small heat shock proteins (sHsps) family, namely Hsp27 and aB-crystallin, are present in Lewy bodies. sHsps also provide strong protection in aSyn-mediated toxicity models. However, the mechanism of sHsp-mediated protective effect and its importance in Lewy body formation are not well understood. We have previously demonstrated that the sHsps function by forming co-assemblies with aggregation-prone proteins. Here, it is hypothesized that sHsps prevent toxicity of aSyn oligomers by co-assembling to form non-toxic inclusions (like Lewy bodies). We propose to test the effect of Hsp27 and aB-crystallin on the aggregation and toxicity of aSyn in a cell culture system. The proposed research will elucidate the molecular mechanisms of sHsps in regulating aSyn aggregation and its neurotoxicity thereby facilitating development of novel therapeutic strategies for PD. ? Parkinson's disease (PD) is the most common neurodegenerative motor disorder, which is characterized by the presence of Lewy bodies in dopaminergic neurons of substantia nigra. Despite the identification of several genes that increase the risk for PD, the disease mechanism is not well understood, thus hindering discovery of therapeutics. In this proposal we will examine the importance of an integral component of Lewy bodies, the small heat shock proteins, to illuminate novel therapeutic avenues. ? ? ?
|Ojha, Juhi; Masilamoni, Gunasingh; Dunlap, David et al. (2011) Sequestration of toxic oligomers by HspB1 as a cytoprotective mechanism. Mol Cell Biol 31:3146-57|