Modulation of SLP-2 expression protects against alpha-synuclein neuropathology by mitigating mitochondrial dysfunction

Cyril Bolduc; Maria Paulina Castelo Rueda; Marina Lorente Picón; Giovanna Gentile; Sreehari Kalvakuri; Victoria Soto Linan; Alessandra Zanon; Sofien Laouafa; Martin Lang; Alexandros Α. Lavdas; Valentina Gilmozzi; Greta Bernardo; Vincent Coulombe; Charles Gora; Modesto R. Peralta; Véronique Rioux; Claudia Honisch; Peter Paul Pramstaller; Paolo Ruzza; Elena Ziviani; Rolf Bodmer; Andrew A. Hicks; Martin Parent; Jorge Soliz; Vincent Joseph; Irene Pichler; Martin Lévesque

doi:10.1101/2025.06.13.659577

NeurosciencebioRxivJun 13, 2025

Preprint

Modulation of SLP-2 expression protects against alpha-synuclein neuropathology by mitigating mitochondrial dysfunction

Cyril Bolduc iD, Maria Paulina Castelo Rueda iD, Marina Lorente Picón iD, Giovanna Gentile iD, Sreehari Kalvakuri iD, Victoria Soto Linan iD, Alessandra Zanon iD, Sofien Laouafa, Martin Lang iD, Alexandros Α. Lavdas iD, Valentina Gilmozzi iD, Greta Bernardo iD, Vincent Coulombe, Charles Gora iD, Modesto R. Peralta, Véronique Rioux iD, Claudia Honisch iD, Peter Paul Pramstaller iD, Paolo Ruzza iD, Elena Ziviani iD, Rolf Bodmer iD, Andrew A. Hicks iD, Martin Parent iD, Jorge Soliz iD, Vincent Joseph iD, , Martin Lévesque iD

Abstract

Parkinsons Disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and the accumulation of alpha-synuclein (Syn)-rich aggregates known as Lewy bodies. Mitochondrial dysfunction is a key contributor to PD pathology, and mitochondrial defects are part of the pathogenic mechanisms induced by Syn. Stomatin-Like protein 2 (SLP-2) is a mitochondrial scaffold protein that regulates mitochondrial integrity and function. Here, we investigated whether SLP-2 induction can counteract Syn-induced mitochondrial dysfunction and neurodegeneration. We found that SLP-2 levels were reduced in human PD brains and an A53T Syn mouse model. Mild overexpression of SLP-2 improved mitochondrial function, reduced oxidative stress, and prevented Syn-mitochondria interactions in human iPSC-derived neurons. In vivo, SLP-2 overexpression protected dopaminergic neurons and motor function, while its depletion exacerbated degeneration and motor deficits in both mouse and Drosophila models. These findings suggest SLP-2 as a key regulator of mitochondrial resilience and a potential therapeutic target for PD and alpha-synucleinopathies.

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