Modulation of amyloid assembly by chaperone-like proteins
Soluble proteins have an inherent propensity to undergo altered protein folding, forming cross-B sheet-rich structures called amyloids. Amyloid fibrils have gained significant attention due to their involvement in neurodegenerative disorders. Parkinson's disease (PD) is one of the most common movement disorders and the fastest-growing age-related neurological disorder. It is characterized by progressive loss of dopaminergic neurons in substantia nigra due to the accumulation of a-synuclein amyloid fibrils leading to the formation of Lewy bodies. Co-aggregation of a-synuclein with other amyloidogenic proteins such as amyloid-B, Tau, and IAPP contributes to the pathophysiology and severity of PD, suggesting that PD progression is associated with other neurological disorders such as Alzheimer's and Huntington's and non-neurological diseases such as Type 2 diabetes and systemic diseases where amyloid deposits can be found in multiple organs including liver, kidney, and heart. An intricate machinery of chaperones and chaperone-like proteins keeps a check on protein aggregation and amyloid formation. However, these guardians lose their properties with age, and proteins such as a-synuclein accumulate in cells. Understanding the role of chaperone-like proteins as amyloid modulators will help in the early diagnosis of disease and present a novel approach to mitigate amyloid burden in neurodegenerative disease. Using bioinformatics tools, we have rationally identified human B-sheet rich proteins that have the potential to act as chaperone-like proteins to inhibit amyloid assembly. These proteins possess remarkable structural similarity, with 50-60% of the structure contributed by B-sheets. We speculated that the B-sheet-rich regions in the proteins may present a scaffold to the growing chain of aggregates, which is incompetent for maturing into amyloid fibrils. We have taken a multi-disciplinary approach involving microbiology, biochemistry, biophysics, molecular and cellular biology tools to decipher the mechanism of amyloid inhibition by chaperone-like proteins. We demonstrated that sub-stoichiometric ratios of CLP drive a-synuclein into soluble off-pathway aggregates incompetent of making amyloids under in vitro conditions. We believe that unraveling the potential of chaperone-like proteins to alleviate amyloid burden will pave the way for future therapeutics to treat neurodegenerative diseases.
Hosted by Professor Zheng Shi
~Coffee/tea will be served prior to the lecture~