Bernardo, G. | bioRxiv Science

bioRxiv2025

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

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.

neuroscience↗

bioRxiv2023

USP8 inhibition promotes Parkin-independent mitophagy in the Drosophila brain and in human neurons

Stress-induced mitophagy, a tightly regulated process that targets dysfunctional mitochondria for autophagy-dependent degradation, mainly relays on two proteins, PINK1 and Parkin, which genes are mutated in some forms of familiar Parkinsons Disease (PD). Upon mitochondrial damage, the protein kinase PINK1 accumulates on the organelle surface where it controls the recruitment of the E3-ubiquitin ligase Parkin. On mitochondria, Parkin ubiquitinates a subset of mitochondrial resident proteins located on the outer mitochondrial membrane, leading to the recruitment of downstream cytosolic autophagic adaptors, and subsequent autophagosome formation. Importantly, PINK1/Parkin-independent mitophagy pathways also exist that can be counteracted by specific deubiquitinating enzymes (DUBs). Downregulation of these specific DUBs can presumably enhances basal mitophagy, and be beneficial in models in which accumulation of defective mitochondria is implicated. Among these DUBs, USP8 is an interesting target because of its role in the endosomal pathway and autophagy, and its beneficial effects, when inhibited, in models of neurodegeneration. Based on this, we evaluated autophagy and mitophagy levels when USP8 activity is altered. We used genetic approaches in D. melanogaster to measure autophagy and mitophagy in vivo, and complementary in vitro approaches to investigate the molecular pathway that regulates mitophagy via USP8. We found an inverse correlation between basal mitophagy and USP8 levels, in that inhibition of USP8 correlates with increased Parkin-independent mitophagy. These results suggest the existence of a yet uncharacterized mitophagic pathway that is inhibited by USP8.

cell biology↗