Objective: To exploit the potential function of the risk gene Slc2a13 in PD progression.

Background: 越来越多的证据证实了总体遗传位点和候选基因对帕金森病的贡献，以及两个最确定的风险基因，即α-突触核蛋白（Snca）和富含亮氨酸的重复激酶2（Lrrk2）。Slc2a13 编码哺乳动物肌醇转运蛋白，被认为是一种群体依赖性风险基因。越来越多的证据支持这样一种观点，即 Slc2a13 活性的改变强调了 PD 的发展。剖析转运蛋白活性降低如何导致多巴胺能神经元变性和丧失，可能会进一步加深我们对功能的理解。

Method: A total of 338 cases with sporadic PD and 252 healthy ethnically matched control subjects, all Han Chinese, were enrolled in central China. Genomic DNA was extracted from peripheral blood using a whole-blood DNA extraction kit for next-generation sequencing. Male mice were randomly divided into 4 groups and received the intraperitoneal injection of saline or MPTP for consecutive 1, 3, 7 days. Molecular biology experiments were finished after the behavior tests and sacrifice.

Results: We first did a seed association study in a Han cohort from central China (n=590). Twenty-one SNP markers were chosen based on the selection criteria. Table 1 showed rs1994090 in Slc2a13 had the most significant association in the gender-mixed model (nominal P=6.8×10^-8, OR=3.43; P=2.5×10^-4, OR=3.11 for males and P=5.0×10^-4, OR=3.95 for females).

Immunofluorescence images of mouse brain demonstrated the coexpressions of SLC2A13 with SNCA and LRRK2 in nigral dopamine neurons (Figure 1a,b),  which was consistent with RNA-scope figures (Figure 1b,d). We also investigated whether altered SLC2A13 activity was associated with PD in a MPTP-induced mouse model. Cellular staining and behaviour tests results showed neurodegeneration (Figure 2a-c). During the seven days, SLC2A13 expression gradually decreased(Figure 2d,e) and statistically, the decrease was detected on Day1, a day earlier than the movement manifestations (Figure 2f,g).

Conclusion: Slc2a13, confers a risk gene for Asian PD, co-expressed with the interacting and endogenous risk genes Snca and Lrrk2, is associated with dopamine neurons loss and abnormal motor function.

Allelic associations with PD in central China

Co-expressions of SLC2A13 with SNCA and LRRK2

Down-regulation of SLC2A13 in a PD mouse model

References: Rizig, M. et al. Identification of genetic risk loci and causal insights associated with Parkinson’s disease in African and African admixed populations: a genome-wide
association study. Lancet Neurol 22, 1015-1025 (2023).
Farrow, S.L. et al. Establishing gene regulatory networks from Parkinson’s disease risk loci. Brain 145, 2422-2435 (2022).
Li, C. et al. Mutation analysis of seven SLC family transporters for early-onset Parkinson’s disease in Chinese population. Neurobiol Aging 103, 152.e1-152.e6 (2021).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/slc2a13-a-risk-gene-for-parkinsons-disease-associated-with-snca-and-lrrk2/