AI Article Synopsis

  • α-synuclein (α-syn), which accumulates in Lewy body inclusions observed in Parkinson's disease, exists in different states influencing synaptic vesicle release, but its membrane-binding mechanisms remain unclear.
  • Protein kinase R (PKR) phosphorylates α-syn at key residues, particularly Thr64 and Thr72, which reduces its binding to lipid membranes and affects its interactions with synaptic vesicles.
  • Modified α-syn with these phosphomimetic mutations not only prevents aggregation and propagation of toxic α-syn forms but could also provide a target for therapeutic strategies in diseases characterized by α-syn pathology.

Article Abstract

Aggregated α-synuclein (α-syn) accumulates in the neuronal Lewy body (LB) inclusions in Parkinson's disease (PD) and LB dementia. Yet, under nonpathological conditions, monomeric α-syn is hypothesized to exist in an equilibrium between disordered cytosolic- and partially α-helical lipid-bound states: a feature presumably important in synaptic vesicle release machinery. The exact underlying role of α-syn in these processes, and the mechanisms regulating membrane-binding of α-syn remains poorly understood. Herein we demonstrate that Protein kinase R (PKR) can phosphorylate α-syn at several Ser/Thr residues located in the membrane-binding region that is essential for α-syn's vesicle-interactions. α-Syn phosphorylated by PKR or α-syn isolated from PKR overexpressing cells, exhibit decreased binding to lipid membranes. Phosphorylation of Thr64 and Thr72 appears as the major contributor to this effect, as the phosphomimetic Thr64Glu/Thr72Glu-α-syn mutant displays reduced overall attachment to brain vesicles due to a decrease in vesicle-affinity of the last two thirds of α-syn's membrane binding region. This allows enhancement of the "double-anchor" vesicle-binding mechanism that tethers two vesicles and thus promote the clustering of presynaptic vesicles in vitro. Furthermore, phosphomimetic Thr64Glu/Thr72Glu-α-syn inhibits α-syn oligomerization and completely abolishes nucleation, elongation, and seeding of α-syn fibrillation in vitro and in cells, and prevents trans-synaptic spreading of aggregated α-syn pathology in organotypic hippocampal slice cultures. Overall, our findings demonstrate that normal and abnormal functions of α-syn, like membrane-binding, synaptic vesicle clustering and aggregation can be regulated by phosphorylation, e.g., via PKR. Mechanisms that could potentially be modulated for the benefit of patients suffering from α-syn aggregate-related diseases.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9802061PMC
http://dx.doi.org/10.1093/pnasnexus/pgac259DOI Listing

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