Journal Article

DZNE-2023-01192

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Excess phosphoserine-129 α-synuclein induces synaptic vesicle trafficking and declustering defects at a vertebrate synapse.

Wallace, J. N. ; Crockford, Z. C. ; Román-Vendrell, C. ; Brady, E. B. ; Hoffmann, C.DZNE* ; Vargas, K. J. ; Potcoava, M. ; Wegman, M. E. ; Alford, S. T. ; Milovanovic, D.DZNE* ; Morgan, J. R.

2024
American Society for Cell Biology Bethesda, Md.

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Please use a persistent id in citations: doi:10.1091/mbc.E23-07-0269

Abstract: α-Synuclein is a presynaptic protein that regulates synaptic vesicle (SV) trafficking. In Parkinson's disease (PD) and dementia with Lewy bodies (DLB), α-synuclein aberrantly accumulates throughout neurons, including at synapses. During neuronal activity, α-synuclein is reversibly phosphorylated at serine 129 (pS129). While pS129 comprises ∼4% of total α-synuclein under physiological conditions, it dramatically increases in PD and DLB brains. The impacts of excess pS129 on synaptic function are currently unknown. We show here that compared with wild-type (WT) α-synuclein, pS129 exhibits increased binding and oligomerization on synaptic membranes and enhanced vesicle 'microclustering' in vitro. Moreover, when acutely injected into lamprey reticulospinal axons, excess pS129 α-synuclein robustly localized to synapses and disrupted SV trafficking in an activity-dependent manner, as assessed by ultrastructural analysis. Specifically, pS129 caused a declustering and dispersion of SVs away from the synaptic vicinity, leading to a significant loss of total synaptic membrane. Live imaging further revealed altered SV cycling, as well as microclusters of recently endocytosed SVs moving away from synapses. Thus, excess pS129 caused an activity-dependent inhibition of SV trafficking via altered vesicle clustering/reclustering. This work suggests that accumulation of pS129 at synapses in diseases like PD and DLB could have profound effects on SV dynamics.

Keyword(s): Lampreys (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; Synaptic Vesicles: metabolism (MeSH) ; Phosphoserine: metabolism (MeSH) ; Synapses: metabolism (MeSH) ; Parkinson Disease: metabolism (MeSH) ; Vertebrates: metabolism (MeSH) ; alpha-Synuclein ; Phosphoserine

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Contributing Institute(s):

1. Molecular Neuroscience (AG Milovanovic)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2024

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Database coverage:
; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Web of Science Core Collection

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