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

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• Professor Dennis Selkoe, Harvard Medical School, Center for Neurologic Diseases, Brigham & Women’s Hospital
• Wednesday 13 December 2017, 11:00-12:00
• Department of Chemistry, Cambridge, Pfizer lecture theatre.

If you have a question about this talk, please contact Patrick Flagmeier.

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 beta-protein (Abeta) and alpha-synculein (alphaSyn). We will describe recent work on the effects of natural oligomers of Abeta isolated from AD cortex on iPSC-derived human neurons, including protection by certain antibodies. We will then provide further evidence that alphaSyn 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 alphaSyn 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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