Abstract
Accumulating evidence reveals mitochondrial dysfunction as a key factor in the pathophysiology of Parkinson’s disease (PD), and mitochondrial defects are also part of the pathogenic mechanisms induced by α-synuclein. Stomatin-like protein 2 (SLP-2) is located in the inner mitochondrial membrane, acting as a scaffold regulating mitochondrial function, integrity and bioenergetics. We have identified phenotypes of mitochondrial dysfunction in SNCA mutant iPSC-derived dopaminergic (DA) neurons, including oxygen consumption and oxidative stress, which can be mitigated by a moderate enhancement of SLP-2 expression, thus conferring protection against α-synuclein toxicity. Additionally, targeted SLP-2 overexpression in DA neurons of the substantia nigra pars compacta (SNpc) of an A53T mutant mouse model of PD ameliorated motor deficits by preventing DA denervation in the striatum and the loss of tyrosine hydroxylase-positive cell bodies in the SNpc. SLP-2 represents a novel molecular target able to boost mitochondrial function and neuronal survival for disease modification in PD.