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miR-101a-3p Impairs Synaptic Plasticity and Contributes to Synucleinopathy

Lookup NU author(s): Professor Tiago OuteiroORCiD

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Abstract

BACKGROUND: Synucleinopathies are disorders characterized by the abnormal accumulation of α-synuclein (aSyn). Synaptic compromise is observed in synucleinopathies parallel to aSyn aggregation and is accompanied by transcript deregulation. OBJECTIVE: We sought to identify microRNAs associated with synaptic processes that may contribute to synaptic dysfunction and degeneration in synucleinopathies. METHODS: We performed small RNA-sequencing of midbrain from 6-month-old transgenic mice expressing A30P mutant aSyn, followed by comparative expression analysis. We then used real-time quantitative polymerase chain reaction (qPCR) for validation. Functional analysis was performed in primary neurons by biochemical assays and imaging. RESULTS: We found several deregulated biological processes linked to the synapse. miR-101a-3p was validated as a synaptic miRNA upregulated in aSyn Tg mice and in the cortex of dementia with Lewy bodies patients. Mice and primary cultured neurons overexpressing miR-101a-3p showed downregulation of postsynaptic proteins GABA Ab2 and SAPAP3 and altered dendritic morphology resembling synaptic plasticity impairments and/or synaptic damage. Interestingly, primary cultured neuron exposure to recombinant wild-type aSyn species efficiently increased miR-101a-3p levels. Finally, a dynamic role of miR-101a-3p in synapse plasticity was shown by identifying downregulation of miR-101a-3p in a condition of enhanced synaptic plasticity modelled in Wt animals housed in enriched environment. CONCLUSION: To conclude, we correlated pathologic aSyn with high levels of miR-101a-3p and a novel dynamic role of the miRNA in synaptic plasticity.

Publication metadata

Author(s): Xylaki M, Paiva I, Al-Azzani M, Gerhardt E, Jain G, Islam MR, Vasili E, Wassouf Z, Schulze-Hentrich JM, Fischer A, Outeiro TF

Publication type: Article

Publication status: Published

Journal: Journal of Parkinson's Disease

Year: 2023

Volume: 13

Issue: 2

Pages: 179-196

Online publication date: 14/03/2023

Acceptance date: 05/01/2023

Date deposited: 04/04/2023

ISSN (print): 1877-7171

ISSN (electronic): 1877-718X

Publisher: IOS Press

URL: https://doi.org/10.3233/JPD-225055

DOI: 10.3233/JPD-225055

PubMed id: 36744345

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