Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction

Liu, Zhenhua; Yang, Nannan; Dong, Jie; Tian, Wen; Chang, Lisa; Ma, Jinghong; Guo, Jifeng; Tan, Jieqiong; Dong, Ao; He, Kaikai; Zhou, Jingheng; Çınar, Reşat; Wu, Jihong; Salinas, Armando G.; Sun, Lixin; Kumar, Mantosh; Sullivan, Breanna T; Oldham, Braden; Pitz, Vanessa; Makarious, Mary B; Ding, Jinhui; Kung, Justin; Xie, Chengsong; Hawes, Sarah; Wang, Lupeng; Wang, Tao; Chan, Piu; Zhang, Zhuohua; Chen, Shengdi; Lovinger, David M.; Blauwendraat, Cornelis; Singleton, Andrew B.; Cui, Guohong; Li, Yulong; Cai, Huaibin; Tang, Beisha

doi:10.1038/s41467-022-31168-9

Cited by 32 publications

(27 citation statements)

References 77 publications

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“…Although pathogenic mutations in disease-causing genes play essential roles in PD, few patients carry pathogenic mutations 5,6 . Common variants with small effect size can be detected via genome-wide association studies (GWASs), and have been shown to affect a large proportion of genetic predisposition of PD 7 .…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson’s disease in Chinese population

Pan

et al. 2023

npj Parkinsons Dis.

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Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson’s disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (Pcombined = 1.47 × 10−9) with low allele frequency, four previously reported risk variants (NUCKS1/RAB29-rs11557080, SNCA-rs356182, FYN-rs997368, and VPS13C-rs2251086), as well as three risk variants in LRRK2 coding region (A419V, R1628P, and G2385R) with genome-wide significance (P < 5 × 10−8) for PD in Chinese population. Moreover, of the reported genome-wide significant risk variants found mostly in European ancestry populations, the correlation coefficient (rb) of effect size accounting for sampling errors was 0.91 between datasets and 63.6% attained P < 0.05 in Chinese population. Accordingly, we estimated a heritability of 0.14–0.18 for PD, and a moderate genetic correlation between European ancestry and Chinese populations (rg = 0.47, se = 0.21). Polygenic risk score (PRS) analysis revealed that individuals with PRS values in the highest quartile had a 3.9-fold higher risk of developing PD than the lowest quartile. In conclusion, the present GWAS identified PD-associated variants in Chinese population, as well as genetic factors shared among distant populations. Our findings shed light on the genetic homogeneity and heterogeneity of PD in different ethnic groups and suggested WGS might continue to improve our understanding of the genetic architecture of PD.

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Section: Introductionmentioning

confidence: 99%

Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson’s disease in Chinese population

Pan

et al. 2023

npj Parkinsons Dis.

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“…Stereotaxic surgery was performed as described previously [4]. The location for SN injection was determined according to the distance from bregma: anterior–posterior = −3.1 mm, medial–lateral = ±1.5 mm, dorsal–ventral = −3.9 mm.…”

Section: Methodsmentioning

confidence: 99%

GGC expansions in NOTCH2NLC contribute to Parkinson disease and dopaminergic neuron degeneration

Liu,

Chen,

Xue

et al. 2023

Euro J of Neurology

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Background and purposeThe role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the NOTCH2NLC GGC repeat expansions in a large cohort of patients with PD. We also investigate the role of GGC repeat expansions within NOTCH2NLC in the dopaminergic neurodegeneration of SN.MethodsA total of 2,522 patients diagnosed with PD and 1,085 health controls were analyzed for the repeat expansions of NOTCH2NLC by repeat‐primed PCR and GC‐rich PCR assay. Furthermore, the effects of GGC repeat expansions in NOTCH2NLC on dopaminergic neurons were investigated by using recombinant adeno‐associated virus (AAV)‐mediated overexpression of NOTCH2NLC with 98 GGC repeats in the SN of mice by stereotactic injection.ResultsFour PD pedigrees (4/333, 1.2%) and three sporadic PD patients (3/2189, 0.14%) were identified with pathogenic GGC repeat expansions (larger than 60 GGC repeats) in the NOTCH2NLC gene, while eight PD patients and one healthy control were identified with intermediate GGC repeat expansions ranging from 41 to 60 repeats. No significant difference was observed in the distribution of intermediate NOTCH2NLC GGC repeat expansions between PD cases and controls (Fisher's exact test p‐value = 0.29). Skin biopsy showed P62‐positive intranuclear NOTCH2NLC‐polyGlycine (polyG) inclusions in the skin nerve fibers of patient. Expanded GGC repeats in NOTCH2NLC produced widespread intranuclear and perinuclear polyG inclusions, which led to a severe loss of dopaminergic neurons in the SN. Consistently, polyG inclusions were presented in the SN of EIIa‐NOTCH2NLC‐(GGC)98 transgenic mice and also led to dopaminergic neuron loss in the SN.ConclusionsOverall, our findings provide strong evidence that GGC repeat expansions within NOTCH2NLC contribute to the pathogenesis of PD and cause degeneration of nigral dopaminergic neurons.

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“…Christelle Tesson, PhD, 1 Mohamed Sofiane Bouchetara, MD, 2 Mélanie Ferrien, MSc, 1 Suzanne Lesage, PhD, 1 and Alexis Brice, MD…”

Section: Ethical Compliance Statementmentioning

confidence: 99%

Identification of a DAGLB Mutation in a Non‐Chinese Patient with Parkinson's Disease

et al. 2023

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Liu and colleagues 1 recently reported that biallelic mutations in DAGLB are responsible for autosomal recessive early-onset Parkinson's disease (AR-EO-PD). They first identified a homozygous DAGLB splice-site mutation in a consanguineous family with two affected siblings by combining homozygosity mapping and whole-exome sequencing. Through exome data mining in a large cohort of 1741 unrelated cases with PD, they identified three additional mutated index cases. All six patients were of Chinese origin and presented typical EO-PD (≤40 years) with a good response to levodopa. No additional cases outside of China have been reported so far.To assess the causal role of pathogenic variants in DAGLB in our French cohort, we used data mining in the exomes of 55 families with AR-PD (n = 88 cases) and 629 isolated EO-PD cases (Appendix S1). We identified a homozygous p.-Pro357Leu missense variant in a single consanguineous PD case (Fig. 1A). This mutation, predicted to be deleterious by 13 of 18 prediction software tested (Supporting Information Table S1 in Appendix S1), affects a conserved amino acid local-

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Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction

Cited by 32 publications

References 77 publications

Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson’s disease in Chinese population

Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson’s disease in Chinese population

GGC expansions in NOTCH2NLC contribute to Parkinson disease and dopaminergic neuron degeneration

Identification of a DAGLB Mutation in a Non‐Chinese Patient with Parkinson's Disease

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