MUL1 gene polymorphisms and Parkinson’s disease risk

Abstract

| INTRODUC TI ONParkinson's disease (PD) is the second most common neurodegenerative disorder worldwide characterized by dopaminergic neuron loss in the substantia nigra. 1 PD expresses as some motor symptoms (MS) like tremors, slowness, rigidity, as well as some non-motor symptoms (NMS) include dementia, depression, constipation, et al 2,3 Although drugs can help to release the pain and movement disorder, PD cannot be cured or halted at present. 4 Recently, several genome-wide association studies (GWAs) have found some multiple risk loci for PD, which may pave a road to future gene therapy. 5,6 Mitochondrial ubiquitin ligase 1 (MUL1), also known as RNF218, C1orf166, growth inhibition and death E3 ligase (GIDE), mitochondrial-anchored protein ligase (MAPL), and mitochondrial ubiquitin ligase activator of NF-kB (MULAN), is an E3 protein ligase. 7 Well known to stabilize Drp1 and degrade Mfn, MUL1 expression results in smaller and more fragmented mitochondria, which is achieved by small ubiquitin-like modifier (SUMO) ligase activity and ubiquitin ligase activity, and can lead to apoptosis. 7,8 When over or under expressed, MUL1 can slow or accelerate cell growth, respectively, via pathways involving caspases activation and c-Jun N-terminal kinase (JNK) activation which can induce apoptosis. 9 Recent researches indicated that MUL1 may play a key role in PD pathogenesis. Jina Yun and his team found the MUL1 pathway could help maintain mitochondrial integrity by compensating for loss of PINK1/parkin and ameliorate PD motor symptoms in drosophila and mammals. 4,10 Another research in mice uncovered that suppression of MUL1 expression in VPS35-deficient DA neurons could restore PD-related defects, including mitochondrial fragmentation and DA neuronal loss. 11 These results certified that MUL1 may act as an individualized therapeutic gene target for PD treatment. Although many studies have been conducted to explore the structure and function of MUL1 in mitochondria, 8,9 there are few reports on the relationship between MUL1 genetic variations and PD pathogenesis, which is more clinically useful. With this in mind, we conducted a case-control study in a Chinese population to evaluate the possible association between single nucleotide polymorphisms (SNPs) in MUL1 gene and PD development.Objectives: Parkinson's disease (PD) is afflicting millions of patients worldwide, and gene therapy may be a hope for cure. Recent researches have shown that MUL1 may play a key role in PD pathogenesis, but no specific genetic variants have been identified. This study was aimed to verify the hypothesis that variants in MUL1 gene were associated with PD risk in a Chinese cohort.Methods: Ten single nucleotide polymorphisms of the MUL1 gene were genotyped through Sanger sequencing in a case-control study containing 100 PD patients and 100 controls matched for age and gender. Results: Our results showed that rs529974 in MUL1 gene was significantly associated with the risk of PD. The allele T in rs529974(+) caused an additional PD tendency (O...

Microarray Genotyping Identifies New Loci Associated with Dementia in Parkinson’s Disease

“…There were few studies investigating the role of MUL1 in the development of dementia in PD, and one case-control study conducted in China showed that MUL1 SNP rs529974 was correlated with the development of PD [ 30 ]. MUL1 encodes mitochondrial ubiquitin ligase 1, a mitochondrial E3 protein ligase that regulates mitofusin.…”

Mitochondrial and Organellar Crosstalk in Parkinson’s Disease

“…Deletion of VPS35 gene in SH-SY5Y and NLT cell lines causes intracellular accumulation of a-syn (Tang et al, 2015). A separate report, in a Chinese cohort study, showed that the gene MUL1 is a risk factor for PD (Taximaimaiti and Li, 2019). Another protein, MIRO1, a Rho GTPase gets localized both in the peroxisomes and mitochondria in mammals (Castro et al, 2018;Okumoto et al, 2018;Farr e et al, 2019).…”

Mitochondrial E3 ubiquitin ligase 1 (MUL1) as a novel therapeutic target for diseases associated with mitochondrial dysfunction

“…Overexpression of MUL1 in the fruit fly model suppresses the PD phenotype caused by loss of PINK or PARKIN 32 . Therefore, endogenous MUL1 levels in PINK/PARKIN mutants would exert a compensatory role 32,60 . This compensatory effect may be explained because both MUL1 and PARKIN are E3 ligases that ubiquitinate Mfn2 for degradation.…”

“…The T allele of rs529974 located in the 3′‐untranslated regions was a risk factor for PD, whereas the C allele of rs529974 was shown to be a protective factor. Thus, mutations in MUL1 are a promising blood biomarker for the early diagnosis of PD 60 . MUL1 is also implicated in some behavioral symptoms of PD, such as sleep disturbances, which could exacerbate disease progression, and nonmotor symptoms, such as altered circadian rhythms of blood pressure and core body temperature 59 …”

“…58 MUL1 is considered a novel therapeutic target in PD, the second most common neurodegenerative disorder, characterized by the loss of dopaminergic (DA) neurons in the substantia nigra. 32,49,60 Impaired mitophagy due to mutations in PINK/PARKIN leads to autosomal recessive forms of PD, 32,49,59 and genetic studies in Drosophila have shown that increased Mfn2 or reduced Drp1 levels could also induce a PD phenotype. 32 Overexpression of MUL1 in the fruit fly model suppresses the PD phenotype caused by loss of PINK or PARKIN.…”