Objective: We investigate the relationship between Sortilin-related receptor (SORL1) gene and PD, along with their functional implications.

Background: Parkinson’s disease (PD) is a common neurodegenerative disease with unknown etiology and pathogenesis. Aging, genetic and environmental factors play essential roles in PD pathogenesis [1]. The SORL1 gene encodes a 250 kD transmembrane protein known as the sortilin-related receptor which mediates the transport of a variety of proteins from endosomes to the cell membrane or Golgi apparatus and is crucial for preserving normal cellular functions [2]. Studies have found SORL1 gene associated with Alzheimer’s disease[3]. Interestingly, study have examined the association between common variants of the SORL1 gene and PD [4]. However, the associations between SORL1 genetic variants and PD, as well as the underlying molecular mechanism remain unclear.

Method: We analyzed the relationship between the SORL1 variants and PD using two next generation sequencing datasets, encompassing 3,959 PD patients and 2,931 controls. We characterized both rare and common variants, and the clinical characteristics of patients. To explore potential pathogenic mechanisms, we examined mitochondrial function, endo-lysosomal function and the status of α-synuclein aggregation in SORL1 knockout cell lines.

Results: Our analysis unveiled a significant collective association for missense variants (P = 0.034) and likely damaging variants (P = 0.032) within the SORL1 gene. The allele-based analysis identified over 30 variants potentially linked to PD (P < 0.05). Compared to patients without SORL1 variants, those with SORL1 variants displayed an earlier age-at-onset (AAO) (P = 0.001).72 Notably, we identified a homozygous variant originating from a consanguineous PD family. Interestingly, alterations in SORL1 mRNA expression were observed in whole blood and substantia nigra of PD patients. Functionally, we found that SORL1-deficiency led to mitochondrial fragmentation and dysfunction, endo-lysosomal dysfunction and α-synuclein aggregation, with the overexpression of the mutation providing no ameliorative effects.

Conclusion: We established a link between the SORL1 variants associated with PD and mitochondrial dysfunction, endo-lysosomal dysfunction, and α-synuclein aggregation, which provide novel insights into the pathogenesis of PD and targets for potential diagnostic biomarker development.

References: [1] Morris HR, Spillantini MG, Sue CM, Williams-Gray CH. The pathogenesis of Parkinson’s disease. Lancet. 2024;403(10423):293-304.
[2] Andersen O M, Rudolph I M, Willnow T E. Risk factor SORL1: from genetic association to functional validation in Alzheimer’s disease. Acta Neuropathol. 2016, 132(5): 653-65.
[3] Schramm C, Charbonnier C, Zarea A, et al. Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes. Genome Med. 2022, 14(1): 69.
[4] Maple-Grodem J, Chung J, Lunde K A, et al. Alzheimer disease associated variants in SORL1 accelerate dementia development in Parkinson disease. Neurosci Lett. 2018, 674: 123-6.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsons-disease-associated-sorl1-variants-impair-mitochondrial-and-endo-lysosomal-function/