MITOCHONDRIAL-DERIVED PEPTIDE, SHLP2, A NOVEL PROTECTIVE FACTOR IN PARKINSON’S DISEASE

Mitochondrial DNA (mtDNA) variants are associated with a wide range of diseases of aging, from diabetes to Alzheimer’s, as well as with longevity itself. However, to date, little work has thoroughly examined the functional roles of mtDNA variants in such age-related diseases or the therapeutic potential of mitochondrial-derived peptides (MDPs) in these conditions. Our lab hypothesizes that mtDNA SNPs could affect MDPs, and we recently showed that a mtDNA SNP is associated with reduced circulating levels of an MDP called humanin and with cognitive decline. How other mtDNA SNPs affect MDPs and disease risk has yet to be analyzed. Remarkably, a recent paper showed a mtDNA SNP (m.2158 T>C) reduces the risk of Parkinson’s disease (PD). Of note, this SNP changes lysine (K) 4 to arginine (R) of a MDP called SHLP2, which is encoded by the 16S rRNA region of the mtDNA. SHLP2 acts as a neuroprotective factor and as a metabolic regulator. We hypothesized that K4R SHLP2 – produced by individuals who carry mtDNA m.2158 T>C – is a protective factor for Parkinson’s disease. Cycloheximide-treated pulse-chase experiments additionally showed that K4R SHLP2 is more stable than WT SHLP2. WT SHLP2 has a polyubiquitination whereas K4R SHLP2 diminish the polyubiquitination. K4R SHLP2 more potently inhibits PD toxin (MPP+) induced apoptosis in neuronal cells. K4R SHLP2 reverse the mitochondrial membrane potential loss and mitochondria respiration defect in TFAM heterozygous knockout MEFs. Altogether, SHLP2 has the therapeutic potential as a precision medicine in PD.

Regional mtDNA SNP differentiation in European Atlantic salmon (Salmo salar): an assessment of potential utility for determination of natal origin

Verspoor, E., Consuegra, S., Fridjonsson, O., Hjorleifsdottir, S., Knox, D., Olafsson, K., Tompsett, S., Wennevik, V., and Garciá de Leániz, C. 2012. Regional mtDNA SNP differentiation in European Atlantic salmon (Salmo salar): an assessment of potential utility for determination of natal origin. – ICES Journal of Marine Science, 69: 1625–1636. The Atlantic salmon, Salmo salar, shows geographically structured differentiation at various classes of molecular genetic variation, among and within river stocks. Nuclear microsatellite locus variation at multiple loci has been exploited for more than a decade as a marker for the continental origin of fish caught at sea in distant-water fisheries. However, a simpler, more cost-effective, but still accurate, assignment can be obtained using a single microsatellite locus in combination with a mitochondrial DNA (mtDNA) single-nucleotide polymorphism (SNP) detected by restriction enzyme digestion. Following on from this, a preliminary study was made of the potential for using mtDNA SNP variation to enhance the resolving power and cost-effectiveness of within-continent assignment of European salmon as determined using microsatellites. Variation in 20 mtDNA regions, encompassing ∼43% of this genome, in 330 salmon from 29 rivers across Europe, was analysed. High levels of inter-individual and inter-river variation were found, as well as evidence of regional differentiation paralleling observed microsatellite differentiation. The observations indicate scope for using mtDNA SNPs along with microsatellites for genetically based assignment of European salmon to region and river of natal origin, but further study is needed.