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

Parkinson’s Disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and the accumulation of alpha-synuclein (αSyn)-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 αSyn. 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 αSyn-induced mitochondrial dysfunction and neurodegeneration. We found that SLP-2 levels were reduced in human PD brains and an A53T αSyn mouse model. Mild overexpression of SLP-2 improved mitochondrial function, reduced oxidative stress, and prevented αSyn-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.