Abstract
One of the main histological hallmarks in Parkinson’s disease (PD) is the apparition of abnormal protein aggregates, mainly constituted by α-synuclein (α-syn) known as Lewy bodies. These structures are involved in toxic processes leading to mitochondrial dysfunction and increase the vulnerability of dopaminergic neurons to degeneration. OBJECTIVE: Stomatin-like protein 2 (SLP-2) is a protein located in the inner mitochondrial membrane and acts as a membrane scaffold regulating mitochondrial functions, integrity and bioenergetics. In this study, we tested the neuroprotective potential of SLP-2 in PD cells and mice models. Our hypothesis is that SLP-2 overexpression will protect dopaminergic neurons against α-syn toxicity and associated locomotion impairment. METHODS: We have assessed mitochondrial morphology and indicators of mitochondrial function and stress in SH-SY5Y cells upon overexpression of α-syn. Immunochemistry and fluorescence quantification were also used to measure SLP-2 and phosphoSer129-α-syn levels present in dopaminergic neurons of control and PD human brains. In mice, we used viral-vector based delivery of adeno-associated viruses containing human mutated A53T-α-syn, and we simultaneously overexpressed SLP-2 in the SNc by stereotaxic injections. Motor activity was assessed using the open field test and cylinder test. Dopaminergic cells survival was quantified by stereological counting. RESULTS: Fluorescence intensity measurement in control and PD human brains revealed that SLP-2 expression is decreased in PD samples when compared to control. Upon induction of α-syn expression in vitro, we observed fragmented mitochondrial networks, accompanied by decreased mitochondrial membrane potential and ATP synthesis rate as well as elevated levels of superoxide. Notably, enhancement of SLP-2 expression rescued mitochondrial defects in these cells indicating that SLP-2 is able to mitigate α-syn-induced mitochondrial pathology. In vivo, histological analysis revealed that SLP-2 protects against α-syn toxicity. CONCLUSION: Our preliminary results indicate that SLP-2 expression is decreased in PD human brains. Our results also indicate that overexpression of SLP-2 can protect dopaminergic neurons against α-syn toxicity both in vitro and in vivo. SLP-2 could thus represent a novel therapeutic target for PD.