Physico-Pathologic Mechanisms Involved in Neurodegeneration: Misfolded Protein-Plasma Membrane Interactions

Abstract

Several neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, are characterized by prominent loss of synapses and neurons associated with the presence of abnormally structured or misfolded protein assemblies. Cell-to-cell transfer of misfolded proteins has been proposed for the intra-cerebral propagation of these diseases. When released, misfolded proteins diffuse in the 3D extracellular space before binding to the plasma membrane of neighboring cells, where they diffuse on a 2D plane. This reduction in diffusion dimension and the cell surface molecular crowding promote deleterious interactions with native membrane proteins, favoring clustering and further aggregation of misfolded protein assemblies. These processes open up new avenues for therapeutics development targeting the initial interactions of deleterious proteins with the plasma membrane or the subsequent pathological signaling.

Microglial glutamate release evoked by α‐synuclein aggregates is prevented by dopamine

“…The presence of αSa closely apposed to plasma membranes is coherent with the know ability of amyloid-like structures to bind to cell membrane components (Shrivastava, Aperia, Melki, & Triller, 2017).…”

Clustering of Tau fibrils impairs the synaptic composition of α3‐Na + /K + ‐ ATP ase and AMPA receptors

“…Pathogenic proteins form clusters that act as traps for membrane proteins diffusing at the plasma membrane (Renner et al, 2010;Shrivastava et al, 2013aShrivastava et al, , 2015Shrivastava et al, , 2017Goniotaki et al, 2017). Similarly to Ab oligomers and a-Syn oligomers/fibrils (Renner et al, 2010;Shrivastava et al, 2013aShrivastava et al, , 2015, exogenous Tau fibrils clustered at the plasma membrane in a concentration-and time-dependent manner.…”

Untangling the Prion-Like Misfolding Mechanism for Neurodegenerative Diseases

“…Although the strain concept has been well documented for PrP Sc [77], it is very new referred to A and tau, for which however, strain-dependent pathologies have been also recently reported [78,79]. The distinct surface properties of pathogenic protein assemblies regulate the different affinities for molecules at the cell surface [10]. In this contest, related to the prion-like mechanism of folding/misfolding and spreading, we will focus on the interaction of the specific misfolded protein assemblies, starting from their release from one cell to their binding to the cell surface of neighboring cell, without covering the intercellular transfer by tunnelling nanotubes [80], because this process circumvents the release and uptake routes.…”

“…It is recently emerged the concept of propagating misfolding by which the normal protein, PrP C , becomes misfolded and gain-of-function mechanisms associated with this misfolding not only propagate further PrP C misfolding in neighboring cells, but can also infect other organisms. The ability of protein particles, deriving from misfolding and aggregation of amyloid- (A), tau, synuclein (-syn), superoxide dismutase 1 (SOD1), to transfer from one cell to another, similar to misfolded PrP, accounts for the widespread pathophysiology seen in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) [10]. Thus, the concept of propagating misfolding together with the emerging demonstrations of "cell nonautonomous" mechanism of intercellular transfer of protein inclusions [11,12], represent the basics for "prion-like" disorders definition of AD, PD and ALS.…”