Abstract
α-Synuclein (αS) is a conserved and abundant neuronal protein with unusual structural properties. It appears to partition between folded and unstructured states as well as between membrane-bound and aqueously soluble states. In addition, a switch between monomeric and tetrameric/multimeric states has been observed recently. The precise composition, localization and abundance of the multimeric species are under study and remain unsettled. Yet to interfere with disease pathogenesis, we must dissect how small changes in αS homeostasis may give rise to Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and other human synucleinopathies. Rationally designed αS point mutations that prevent the protein from populating all states within its normal folding repertoire have continued to be instrumental in bringing new insights into its biochemistry in vivo. This review summarizes biochemical and cell biological findings about αS homeostasis from different labs, with a special emphasis on intact-cell approaches that may preserve the complex, metastable native states of αS.
Highlights
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
This review summarizes biochemical and cell biological findings about αS homeostasis from different labs, with a special emphasis on intact-cell approaches that may preserve the complex, metastable native states of αS
Like αS, apolipoproteins interact with lipid membranes via their N-terminal regions and, interestingly, they are the protein class that is over-represented in amyloid diseases: so far four apolipoproteins, SAA, Apo AI, Apo AII, and Apo AIV, have been described in the context of amyloidosis (Sipe et al, 2014)
Summary
This review summarizes biochemical and cell biological findings about αS homeostasis from different labs, with a special emphasis on intact-cell approaches that may preserve the complex, metastable native states of αS Both native and altered αS folding states are of great interest as regards normal biology and the mechanisms, diagnostics and disease-modifying therapeutics of synucleinopathies. A wellrecognized αS species in vitro is the soluble unfolded monomer (Weinreb et al, 1996), and a recent publication showed that this state can persist in considerable part when exogenous unfolded recombinant monomers are delivered into cultured mammalian cells by electroporation (Theillet et al, 2016) This incell liquid phase NMR analysis did not rule out the existence of other αS species, as the method is unable to detect membranebound or multimeric αS forms (Alderson and Bax, 2016). The known fPD/DLB-linked αS missense mutations have been obvious candidates for studying perturbed αS equilibria, but rationally designed variants have been informative as well
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
