Altered conformation of α-synuclein drives dysfunction of synaptic vesicles in a synaptosomal model of Parkinson’s disease

Fonseca‐Ornelas, Luis; Viennet, Thibault; Rovere, Matteo; Jiang, Haiyang; Liu, Lei; Nuber, Silke; Ericsson, Maria; Arthanari, Haribabu; Selkoe, Dennis J.

doi:10.1016/j.celrep.2021.109333

Cited by 29 publications

(22 citation statements)

References 77 publications

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“…Moreover, we showed that transgenic (tg) expression in mice of the E46K mutation that causes PD and dementia with Lewy bodies (DLB), and especially expression of an engineered mutant with two additional E→K substitutions in the adjacent KTK E GV repeat motifs (E35K + E46K + E61K), can produce a striking PD-like motor phenotype with resting tremor and limb and gait deficits responding in part to L-DOPA 23 . These ‘tetramer-abrogating’ tg mice have nigral and cortical αSyn inclusions, increased αSyn pSer129 phosphorylation, decreased dopamine levels, disrupted synaptic ultrastructure, and lysosomal changes resembling those of human PD 16 , 23 , 24 .…”

Section: Introductionmentioning

confidence: 99%

“…Although the precise function of αSyn is still debated, it has become increasingly accepted that at least part of its function in neurons involves the regulation of vesicle trafficking, including during synaptic transmission, for example, by controlling the dilation of the exocytotic fusion pore 14 and chaperoning the assembly of SNARE complexes 15 , 16 . αSyn has long been considered a ‘natively unfolded’ protein in aqueous solution 17 and in cells 18 , despite the widely-replicated finding that unfolded recombinant αSyn readily adopts an α-helical conformation upon binding to the outside of certain highly curved lipid vesicles in vitro 19 .…”

Section: Introductionmentioning

confidence: 99%

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Parkinson-causing mutations in LRRK2 impair the physiological tetramerization of endogenous α-synuclein in human neurons

Fonseca‐Ornelas

Stricker

Soriano-Cruz

et al. 2022

npj Parkinsons Dis.

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α-Synuclein (αSyn) aggregation in Lewy bodies and neurites defines both familial and ‘sporadic’ Parkinson’s disease. We previously identified α-helically folded αSyn tetramers, in addition to the long-known unfolded monomers, in normal cells. PD-causing αSyn mutations decrease the tetramer:monomer (T:M) ratio, associated with αSyn hyperphosphorylation and cytotoxicity in neurons and a motor syndrome of tremor and gait deficits in transgenic mice that responds in part to L-DOPA. Here, we asked whether LRRK2 mutations, the most common genetic cause of cases previously considered sporadic PD, also alter tetramer homeostasis. Patient neurons carrying G2019S, the most prevalent LRRK2 mutation, or R1441C each had decreased T:M ratios and pSer129 hyperphosphorylation of their endogenous αSyn along with increased phosphorylation of Rab10, a widely reported substrate of LRRK2 kinase activity. Two LRRK2 kinase inhibitors normalized the T:M ratio and the hyperphosphorylation in the G2019S and R1441C patient neurons. An inhibitor of stearoyl-CoA desaturase, the rate-limiting enzyme for monounsaturated fatty acid synthesis, also restored the αSyn T:M ratio and reversed pSer129 hyperphosphorylation in both mutants. Coupled with the recent discovery that PD-causing mutations of glucocerebrosidase in Gaucher’s neurons also decrease T:M ratios, our findings indicate that three dominant genetic forms of PD involve life-long destabilization of αSyn physiological tetramers as a common pathogenic mechanism that can occur upstream of progressive neuronal synucleinopathy. Based on αSyn’s finely-tuned interaction with certain vesicles, we hypothesize that the fatty acid composition and fluidity of membranes regulate αSyn’s correct binding to highly curved membranes and subsequent assembly into metastable tetramers.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Parkinson-causing mutations in LRRK2 impair the physiological tetramerization of endogenous α-synuclein in human neurons

Fonseca‐Ornelas

Stricker

Soriano-Cruz

et al. 2022

npj Parkinsons Dis.

Self Cite

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“…A study in 2018 analyzed human neuroblastoma SH-S5Y5 cells and found that both DA-induced oligomeric α-synuclein aggregates and α-synuclein PPFs lead to sequestered levels of VAMP-2 [ 34 ]. In line with this, another group detected decreased protein levels of VAMP2, syntaxin-1, and synaptophysin when exposed to overexpressed human WT α-synuclein in transgenic mice around 12 months old, as well as both the E46K and 3K α-synuclein mutations [ 43 ]. By contrast however, another group reported no changes in the levels of these proteins, despite also using human WT α-syn and a similar analysis technique [ 18 ].…”

Section: Resultsmentioning

confidence: 74%

“…Human post-mortem tissue that was obtained from PDD and DLB patients revealed reduced Rab3A expression levels with a loss of 24–34% identified via WB and a loss of 27–43% identified via the ELISA technique. The research also detected reduced levels in 3k mutant mice [ 43 ]. However by contrast, another group found a 1.3-fold increase in the Rab3a protein levels (30%) in transgenic mice that were expressing the A53T α-synuclein mutation [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

The Effect of Aggregated Alpha Synuclein on Synaptic and Axonal Proteins in Parkinson’s Disease—A Systematic Review

Murphy

McKernan

2022

Biomolecules

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α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson’s disease. Aggregated α-synuclein can impair both synaptic functioning and axonal transport. However, understanding the pathological role that α-synuclein plays at a cellular level is complicated as existing findings are multifaceted and dependent on the mutation, the species, and the quantity of the protein that is involved. This systematic review aims to stratify the research findings to develop a more comprehensive understanding of the role of aggregated α-synuclein on synaptic and axonal proteins in Parkinson’s disease models. A literature search of the PubMed, Scopus, and Web of Science databases was conducted and a total of 39 studies were included for analysis. The review provides evidence for the dysregulation or redistribution of synaptic and axonal proteins due to α-synuclein toxicity. However, due to the high quantity of variables that were used in the research investigations, it was challenging to ascertain exactly what effect α-synuclein has on the expression of the proteins. A more standardized experimental approach regarding the variables that are employed in future studies is crucial so that existing literature can be consolidated. New research involving aggregated α-synuclein at the synapse and regarding axonal transport could be advantageous in guiding new treatment solutions.

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“…Natively unfolded α-synuclein in solution, adopts an α-helical conformation in its N-terminal domain in the presence of membranes with acidic phospholipid headgroups and/or high curvature [ 34 – 36 ]. This interaction of α-synuclein with membranes may normally reduce misfolding into a β-sheet assembly [ 37 ] and/or promote physiological multimers [ 38 , 39 ] that mediate its function in SNARE complex assembly and synaptic vesicle recycling [ 40 ]. On the other hand, the presence of lipids and detergents was also shown to increase the rate of α-synuclein fibril formation [ 41 , 42 ].…”

Section: Initiation Of α-Synuclein Aggregation Entails Aberrant Membr...mentioning

confidence: 99%

Initiation and progression of α-synuclein pathology in Parkinson’s disease

Tofaris

2022

Cell. Mol. Life Sci.

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Abstractα-Synuclein aggregation is a critical molecular process that underpins the pathogenesis of Parkinson’s disease. Aggregates may originate at synaptic terminals as a consequence of aberrant interactions between α-synuclein and lipids or evasion of proteostatic defences. The nature of these interactions is likely to influence the emergence of conformers or strains that in turn could explain the clinical heterogeneity of Parkinson’s disease and related α-synucleinopathies. For neurodegeneration to occur, α-synuclein assemblies need to exhibit seeding competency, i.e. ability to template further aggregation, and toxicity which is at least partly mediated by interference with synaptic vesicle or organelle homeostasis. Given the dynamic and reversible conformational plasticity of α-synuclein, it is possible that seeding competency and cellular toxicity are mediated by assemblies of different structure or size along this continuum. It is currently unknown which α-synuclein assemblies are the most relevant to the human condition but recent advances in the cryo-electron microscopic characterisation of brain-derived fibrils and their assessment in stem cell derived and animal models are likely to facilitate the development of precision therapies or biomarkers. This review summarises the main principles of α-synuclein aggregate initiation and propagation in model systems, and their relevance to clinical translation.

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Altered conformation of α-synuclein drives dysfunction of synaptic vesicles in a synaptosomal model of Parkinson’s disease

Cited by 29 publications

References 77 publications

Parkinson-causing mutations in LRRK2 impair the physiological tetramerization of endogenous α-synuclein in human neurons

Parkinson-causing mutations in LRRK2 impair the physiological tetramerization of endogenous α-synuclein in human neurons

The Effect of Aggregated Alpha Synuclein on Synaptic and Axonal Proteins in Parkinson’s Disease—A Systematic Review

Initiation and progression of α-synuclein pathology in Parkinson’s disease

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