Proteomic profiling reveals the potential mechanisms and regulatory targets of sirtuin 4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s mouse model

Abstract

IntroductionParkinson’s disease (PD), as a common neurodegenerative disease, currently has no effective therapeutic approaches to delay or stop its progression. There is an urgent need to further define its pathogenesis and develop new therapeutic targets. An increasing number of studies have shown that members of the sirtuin (SIRT) family are differentially involved in neurodegenerative diseases, indicating their potential to serve as targets in therapeutic strategies. Mitochondrial SIRT4 possesses multiple enzymatic activities, such as deacetylase, ADP ribosyltransferase, lipoamidase, and deacylase activities, and exhibits different enzymatic activities and target substrates in different tissues and cells; thus, mitochondrial SIRT4 plays an integral role in regulating metabolism. However, the role and mechanism of SIRT4 in PD are not fully understood. This study aimed to investigate the potential mechanism and possible regulatory targets of SIRT4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice.MethodsThe expression of the SIRT4 protein in the MPTP-induced PD mouse mice or key familial Parkinson disease protein 7 knockout (DJ-1 KO) rat was compared against the control group by western blot assay. Afterwards, quantitative proteomics and bioinformatics analyses were performed to identify altered proteins in the vitro model and reveal the possible functional role of SIRT4. The most promising molecular target of SIRT4 were screened and validated by viral transfection, western blot assay and reverse transcription quantitative PCR (RT-qPCR) assays.ResultsThe expression of the SIRT4 protein was found to be altered both in the MPTP-induced PD mouse mice and DJ-1KO rats. Following the viral transfection of SIRT4, a quantitative proteomics analysis identified 5,094 altered proteins in the vitro model, including 213 significantly upregulated proteins and 222 significantly downregulated proteins. The results from bioinformatics analyses indicated that SIRT4 mainly affected the ribosomal pathway, propionate metabolism pathway, peroxisome proliferator-activated receptor (PPAR) signaling pathway and peroxisome pathway in cells, and we screened 25 potential molecular targets. Finally, only fatty acid binding protein 4 (FABP4) in the PPAR signaling pathway was regulated by SIRT4 among the 25 molecules. Importantly, the alterations in FABP4 and PPARγ were verified in the MPTP-induced PD mouse model.DiscussionOur results indicated that FABP4 in the PPAR signaling pathway is the most promising molecular target of SIRT4 in an MPTP-induced mouse model and revealed the possible functional role of SIRT4. This study provides a reference for future drug development and mechanism research with SIRT4 as a target or biomarker.

Metabolic Basis of Circadian Dysfunction in Parkinson’s Disease

“…Furthermore, altered expression in antioxidative genes and FABP4 in the PPAR signaling pathway was observed. Moreover, circadian rhythmicity of SIRT1 was lost [84,85]. SIRT1 is a significant clock component that involves the deacetylation of BMAL1 and PER2 proteins and binds to the CLOCK-BMAL1 complex to affect circadian rhythm and the expression of clock-controlled genes.…”

CoCl2triggered pseudohypoxic stress induces proteasomal degradation of SIRT4viapolyubiquitination of lysines K78 and K299

“…16.540489 doi: bioRxiv preprint of aging-associated diseases [13,14]. This is further emphasized by recent data indicating an involvement of SIRT4 in the onset and development of Parkinson's disease [15]. Human sirtuins localize in multiple subcellular compartments, functioning across them [16][17][18][19][20].…”

CoCl2‐triggered pseudohypoxic stress induces proteasomal degradation of SIRT4 via polyubiquitination of lysines K78 and K299

“…Mitochondrial sirtuins like SIRT3 represent potential targets for the treatment of aging‐associated diseases [13,14]. This is further emphasized by recent data indicating an involvement of SIRT4 in the onset and development of Parkinson's disease [15].…”