Study finds previously unidentified genetic mutation in a small protein provides significant protection against Parkinson’s disease

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In a recent study published in Molecular Psychiatry, researchers explored the effects of a small humanin-like peptide 2 (SHLP2) variant on mitochondrial function.

Study: A naturally occurring variant of SHLP2 is a protective factor in Parkinson’s disease. Image Credit: peterschreiber.media/Shutterstock.com
Study: A naturally occurring variant of SHLP2 is a protective factor in Parkinson’s disease. Image Credit: peterschreiber.media/Shutterstock.com

Background

Mitochondria are implicated in Parkinson’s disease (PD) pathogenesis. Mitochondrial-derived peptides (MDPs) are microproteins encoded from small open reading frames (sORFs) in the mitochondrial DNA (mtDNA). SHLP2 is an MDP with an essential role in multiple cellular processes, and it improves mitochondrial metabolism by increasing biogenesis and respiration and reducing oxidation.

Recent studies link mitochondrial single nucleotide polymorphisms (mtSNPs) within coding regions of MDPs to age-related deficits. For instance, m.2706 A > G, an mtSNP in humanin, predicts reduced circulating levels of humanin and worse cognitive decline. Moreover, another mtSNP, m.2158 T > C, is associated with reduced PD risk, albeit the underlying mechanisms are unknown.

The study and findings

In the present study, researchers explored the effects of the m.2158 T > C allelic form of SHLP2, which replaces lysine with arginine at the fourth position (K4R), on mitochondrial function. Data were obtained from the Health and Retirement Study (HRS) of older Americans aged > 50. The current analysis was restricted to White/Caucasian participants.

In addition, the study included data on 2,772 participants from the Cardiovascular Health Study (CHS) and 3,621 participants from the Framingham Heart Study (FHS). In HRS, FHS, and CHS, multivariable linear regression was used to examine associations between SHLP2 and total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C).

m.2158 T > C was associated with increased TC and LDL-C but not HDL-C. The researchers used a protein variation effect analyzer (PROVEAN) to predict the impact of the K4R substitution. The PROVEAN score for K4R was -3, lower than the predicted cutoff score (-2.5). Thus, the K4R substitution was likely to induce a functional change.

Next, the team compared the predicted structures of SHLP2 with K4R using PEP-FOLD3, a de novo modeling algorithm. The predicted three-dimensional structure of wild-type (WT) SHLP2 revealed a loop-like structure with an alpha helix in the middle. However, the K4R substitution significantly altered the structure, additionally forming a beta-sheet.

SHLP2 was predicted to be a mitochondrial membrane-integrated protein. HEK293 cells transfected with plasmids carrying WT SHLP2 or K4R SHLP2 showed similar mRNA levels but had higher protein levels of the K4R variant than WT SHLP2. Moreover, pulse-chase experiments revealed a higher stability of K4R SHLP2 than WT SHLP2.

Next, the researchers performed ascorbate peroxidase 2 (APEX2) proximity labeling. Notably, APEX2-tagged SHLP2 showed mitochondrial localization, confirming the prediction. Further, the team examined the biotinylation of one of the inner (IMM) and outer mitochondrial membrane (OMM) proteins in SHLP2-APEX2 fusion protein-expressing HEK293 cells treated with hydrogen peroxide and biotin-phenol.

NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), the tested IMM protein, was biotinylated in cells treated with the fusion protein but not those treated with the control. On the other hand, TOM20, the OMM protein, was not biotinylated in cells treated with the fusion protein or control. This suggested that SHLP2 was localized to the IMM. Next, significance analysis of interactome (SAINT) express was applied to the SHLP2-APEX2 dataset, identifying 597 proteins.

Enrichment analysis revealed that proteins were enriched in the tricarboxylic acid (TCA) cycle and mitochondrial complex 1. Further experiments indicated that SHLP2 was directly bound to the proton pumping module of the mitochondrial complex 1. Next, the protective role of SHLP2 against mitochondrial dysfunction was examined using mouse embryonic fibroblasts (MEFs) heterozygous for the mitochondrial transcription factor A (TFAM).

TFAM+/- MEFs showed about 50% reduction in mtDNA copy number. Administration of WT or K4R SHLP2 did not alter TFAM levels. However, K4R SHLP2 exposure increased nicotinamide adenine dinucleotide (NAD+) levels in these cells. Moreover, K4R SHLP2 treatment significantly reduced the number of cells with enlarged mitochondria. In addition, K4R treatment of SH-SY5Y neuronal cells reduced 1-methyl-4-phenylpyridinium (MPP+)-induced cell death.

Finally, C57BL/6 mice were pretreated with WT or K4R SHLP five days before N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced cell death. Administering K4R SHLP2 was protective against the loss of striatal tyrosine hydroxylase expression in MPTP-treated mice. By contrast, WT SHLP2 treatment did not provide similar levels of protection. Nevertheless, both WT and K4R SHLP2 administration rescued MPTP-induced dopamine loss in the striatum.

Conclusions

Taken together, the study showed that m.2158 T > C SNP introduces a K4R substitution in SHLP2. Besides, the team uncovered the protective role of this variant in in vitro and in vivo PD models. They showed that SHLP2 was localized to the IMM, specifically to the proton pumping module of the mitochondrial complex 1.

The authors suggest the protective role of K4R SHLP2 through increased NAD+ levels, given that lower NAD+ levels have been reported to be harmful. Overall, the study provided insights into the functional consequences of m.2158 T > C on SHLP2, suggesting that SHLP2 and its variants are protective against PD.

Journal reference:
Tarun Sai Lomte

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.

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