New insights into protein misfolding in Alzheimer’s and Parkinson’s diseases using in vivo systems

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• Prof Dennis Selkoe, Harvard Medical School and Brigham and Women's Hospital
• Friday 17 February 2017, 14:00-15:00
• Department of Chemistry, Cambridge, Pfizer lecture theatre.

If you have a question about this talk, please contact Priyanka Joshi.

Misfolding and progressive aggregation of specific proteins may be etiologic in several human neurodegenerative diseases. Many studies have examined the process in vitro, resulting in valuable insights, but to what extent findings in relatively pure in vitro systems reflect the situation in the patient’s brain is unclear. Here, we have focused on living cells, mice, and human brain tissue to learn more about the characteristics and bioactivities of various endogenous forms of amyloid β-protein (Aβ) and α-synculein (αSyn). We will describe recent work on the effects of natural oligomers of Aβ isolated from AD cortex on iPSC-derived human neurons, including protection by certain antibodies. We will then provide further evidence that αSyn occurs normally as helical tetramers in intact cells, but these rapidly disassemble upon cell lysis, yielding the unfolded monomers that have been the focus of in vitro studies. Mice expressing tetramer-abrogating αSyn mutations develop nigrostriatal and cortical lesions, decreased tyrosine hydroxylase, and a progressive motor phenotype that includes tremor and gait defects which respond in part to L-DOPA. These new findings have implications for the initiation of PD and other human synucleinopathies and their potential prevention by compounds which stabilize the physiological tetramers.

This talk is part of the Biophysical Seminars series.

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