α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies

Abstract

Significanceα-Synuclein (α-Syn) aggregation underlies neurodegeneration in synucleinopathies. However, the nature of α-Syn aggregates and their toxic mechanisms in human pathology remains elusive. Here, we delineate a role of α-Syn oligomeric aggregates for axonal integrity in human neuronal models of synucleinopathies. α-Syn oligomers disrupt anterograde axonal transport of mitochondria by causing subcellular changes in transport-regulating proteins and energy deficits. An increase of α-Syn oligomers in human neurons finally results in synaptic degeneration. Together, our data provide mechanistic insights of α-Syn oligomeric toxicity in human neurons. Taking into account that α-Syn oligomers and axonal dysfunction are characteristic for early neurodegeneration in synucleinopathies, our data might deliver targets for therapeutic interference with early disease pathology.

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

“…α-synuclein can also bind mitochondria-associated ER membranes (MAM) (Guardia-Laguarta et al, 2014), and evidence indicating that its absence impairs mitochondria lipid composition, function, fusion, and trafficking (Ellis et al, 2005;Faustini et al, 2019) supports that the protein can play a physiological role in the regulation of mitochondrial homeostasis. This hypothesis is in line with findings showing that pathological α-syn aggregates or oligomers produce mitochondria fragmentation, impair mitochondrial trafficking, and lead to respiration failure (Devi et al, 2008;Nakamura et al, 2011;Tapias et al, 2017;Prots et al, 2018;Wang et al, 2019).…”

In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

“…The reduction in anterograde mitochondrial transport has recently been specifically associated with the accumulation of oligomeric species in neuronal iPSC isolated from an individual with SNCA duplication (Prots et al . ).…”

“…Such changes in synaptic integrity are likely early occurring pathological events, as the accumulation of oligomers following α‐Syn over‐expression in human iPSC derived neurons was recently reported to coincide with numerous synaptic structural abnormities alongside a general loss of pre‐synaptic protein expression and axonal fibers (Prots et al . ). Interestingly, high levels of α‐Syn may not only affect neuronal communication via synaptic dysfunction but also via reducing the gap junction intercellular communications (Sung et al .…”

“…The disparity in trafficking lead to the depletion of organelles within distal axonal segments as well as inducing mitochondria fragmentation (Pozo Devoto et al 2017). The reduction in anterograde mitochondrial transport has recently been specifically associated with the accumulation of oligomeric species in neuronal iPSC isolated from an individual with SNCA duplication (Prots et al 2018).…”

Parkinson’s disease associated mutation E46K of α-synuclein triggers the formation of a novel fibril structure

“…The clinical phenotype of E46K patient features rapid and severe disease progression with early onset of the parkinsonism of DLB 11 . Previous studies have shown that the E46K mutation can enhance α -syn fibril formation and α -syn pathology in vitro and in cultured cells 13,17,18 . Solid state NMR study has shown that the E46K mutation causes large conformational changes of the fibril structure 19 .…”