Identification of sixteen novel candidate genes for late onset Parkinson’s disease

Abstract

Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.

Differential Analysis of A-to-I mRNA Edited Sites in Parkinson’s Disease

“…Abnormalities in mRNA editing of these genes could be associated with non-motor symptoms of PD such as anxiety or problems with memory. GIPC1 was recently identified as a gene likely to be involved in the development of PD [ 23 ]. The role of perilipin Plin4 (a coating protein and regulator of intracellular lipid droplets) in neuronal cytotoxicity has also been shown in PD experimental models [ 24 ].…”

Dopamine transporter and synaptic vesicle sorting defects initiate auxilin-linked Parkinson’s disease

“…Loss-of-function, autosomal recessive mutations of the auxilin gene ( PARK19 ) cause juvenile, early-onset PD (Edvardson et al, 2012; Elsayed et al, 2016; Köroğlu et al, 2013; Mittal, 2020; Ng et al, 2020; Olgiati et al, 2016; Ray et al, 2021). A recent study also shows PARK19 mutations in late-onset PD (Gialluisi et al, 2021). In vivo presynaptic dopamine transporter (DAT) imaging on a PARK19 patient revealed DA terminal loss, which supports a parkinsonism diagnosis and suggests that clathrin uncoating deficits impact DA presynaptic sites (Ng et al, 2020).…”

Controlling glutathione entry into mitochondria: potential roles for SLC25A39 in health and (treatment of) disease

“…Among them, several genes seemed to be involved in mitochondrial metabolism and oxidative stress, as e.g., SLC25A39. 4 In addition, SLC25A39 expression in adult dopaminergic neurons of the midbrain could be demonstrated by the same authors. 4 Thus, defects in SLC25A39 induce severe disturbances in the mitochondrial GSH-import machinery contributing to neuronal degeneration.…”

“… 4 In addition, SLC25A39 expression in adult dopaminergic neurons of the midbrain could be demonstrated by the same authors. 4 Thus, defects in SLC25A39 induce severe disturbances in the mitochondrial GSH-import machinery contributing to neuronal degeneration. However, to get further insight in the role of SLC35A39 in the brain, the generation of specific conditional Slc25a39 knockout mice that carry a deletion of Slc25a39 exclusively in neurons or in the central nervous system may further boost our understanding on the roles and in the importance of SLC25A39 in neuronal tissues.…”