Researchers have identified a naturally occurring variant of SHLP2 that may offer protection against Parkinson’s disease (PD). The study, published in Molecular Psychiatry, delves into the functional role of a mitochondrial DNA single nucleotide polymorphism (mtSNP) associated with reduced PD risk, shedding light on potential mechanisms for the protective effect.

The mtSNP in question, m.2158 T > C, affects the small open reading frame encoding SHLP2, resulting in an alternative form of the mitochondrial-derived peptide. Specifically, the variant, known as K4R, demonstrates increased stability compared to the wild-type SHLP2. The study also found that both the wild-type and K4R SHLP2 exhibit enhanced protection against mitochondrial dysfunction in in vitro experiments and confer resistance to a PD-inducing toxin in a mouse model.

Through targeted mass spectrometry, researchers detected specific tryptic fragments of SHLP2 in neuronal cells and demonstrated its binding to mitochondrial complex 1. These findings provide valuable insights into the potential mechanisms by which the mtSNP may reduce the risk of PD, offering a promising avenue for further research into the disease.