Background Common and rare variants of guanosine triphosphate cyclohydrolase 1 ( GCH1 ) gene may play important roles in Parkinson’s disease (PD). However, there is a lack of comprehensive analysis of GCH1 genotypes, especially in non-coding regions. The aim of this study was to explore the genetic characteristics of GCH1 , including rare and common variants in coding and non-coding regions, in a large population of PD patients in Chinese mainland, as well as the phenotypic characteristics of GCH1 variant carriers. Methods In the first cohort of this case-control study, we performed whole-exome sequencing in 1555 patients with early-onset or familial PD and 2234 healthy controls; then in the second cohort, whole-genome sequencing was performed in sporadic late-onset PD samples (1962 patients), as well as 1279 controls. Variants at target GCH1 regions were extracted, and then genetic and detailed phenotypic data were analyzed using regression models and the sequence kernel association test. We also performed a meta-analysis to correlate deleterious GCH1 variants with age at onset (AAO) in PD patients. Results For coding variants, we identified a significant burden of GCH1 deleterious variants in early-onset or familial PD cases compared to controls (1.2% vs 0.1%, P < 0.0001). In the analysis of possible regulatory variants in GCH1 non-coding regions, rs12323905 ( P = 0.001, odds ratio = 1.19, 95%CI 1.07–1.32) was significantly associated with PD, and variant sets in untranslated regions and intron regions, GCH1 brain-specific expression quantitative trait loci, and two possible promoter/enhancer (GH14J054857 and GH14J054880) were suggestively associated with PD. Genotype-phenotype correlation analysis revealed that the carriers of GCH1 deleterious variants manifested younger AAO ( P < 0.0001), and had milder motor symptoms, milder fatigue symptoms and more autonomic nervous dysfunctions. Meta-analysis of six studies demonstrated 6.4-year earlier onset in GCH1 deleterious variant carriers ( P = 0.0009). Conclusions The results highlight the importance of deleterious variants and non-coding variants of GCH1 in PD in Chinese mainland and suggest that GCH1 mutation can influence the PD phenotype, which may help design experimental studies to elucidate the mechanisms of GCH1 in the pathogenesis of PD.

Expansion of the neural progenitor pool in the developing cerebral cortex is crucial for controlling brain size, since proliferation defects have been associated with the pathogenesis of microcephaly in humans. Cell cycle regulators play important roles in proliferation of neural progenitors. Here, we show that the cyclin-dependent kinase inhibitor p21 (also called Cdkn1a and Cip1) negatively regulates proliferation of radial glial cells (RGCs) and intermediate progenitors (IPs) in the embryonic mouse cortex. MicroRNA-17 (miR-17) displays reciprocal expressions with p21 in the developing cortex. Opposite to p21, miR-17 promotes expansion of RGCs and IPs, as demonstrated by overexpressing miR-17 precursors and miR-17 sponges that can knock down the endogenous miR-17. Moreover, p21 is a putative target normally silenced by miR-17. Co-expression of miR-17 with p21 is sufficient to rescue the negative regulation of p21 on progenitor proliferation. Our results indicate a mechanism of controlling the neural progenitor pool, which is to suppress p21 by miR-17 in the developing cortex.

Background There is a lack of large multicenter Parkinson's disease (PD) cohort studies and limited data on the natural history of PD in China. Objectives The objective of this study was to launch the Chinese Parkinson's Disease Registry (CPDR) and to report its protocol, cross‐sectional baseline data, and prospects for a comprehensive observational, longitudinal, multicenter study. Methods The CPDR recruited PD patients from 19 clinical sites across China between January 2018 and December 2020. Clinical data were collected prospectively using at least 17 core assessment scales. Patients were followed up for clinical outcomes through face‐to‐face interviews biennially. Results We launched the CPDR in China based on the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network (PD‐MDCNC). A total of 3148 PD patients were enrolled comprising 1623 men (51.6%) and 1525 women (48.4%). The proportions of early‐onset PD (EOPD, age at onset ≤50 years) and late‐onset PD (LOPD) were 897 (28.5%) and 2251 (71.5%), respectively. Stratification by age at onset showed that EOPD manifested milder motor and nonmotor phenotypes and was related to increased probability of dyskinesia. Comparison across genders suggested a slightly older average age at PD onset, milder motor symptoms, and a higher rate of developing levodopa‐induced dyskinesias in women. Conclusions The CPDR is one of the largest multicenter, observational, longitudinal, and natural history studies of PD in China. It offers an opportunity to expand the understanding of clinical features, genetic, imaging, and biological markers of PD progression. © 2022 International Parkinson and Movement Disorder Society.

Brain morphogenesis requires precise regulation of multiple genes to control specification of distinct neural progenitors (NPs) and neuronal production. Dysregulation of these genes results in severe brain malformation such as macrocephaly and microcephaly. Despite studies of the effect of individual pathogenic genes, the counter-balance between multiple factors in controlling brain size remains unclear. Here we show that cortical deletion of Gli3 results in enlarged brain and folding structures in the cortical midline at the postnatal stage, which is mainly caused by the increased percentage of intermediate progenitors (IPs) and newborn neurons. In addition, dysregulation of neuronal migration also contributes to the folding defects in the cortical midline region. Knockdown of microRNA (miRNA) miR-7 can rescue abnormal brain morphology in Gli3 knockout mice by recovering progenitor specification, neuronal production and migration through a counter-balance of the Gli3 activity. Moreover, miR-7 likely exerts its function through silencing target gene Pax6. Our results indicate that proper brain morphogenesis is an outcome of interactive regulations of multiple molecules such as Gli3 and miR-7. Because miRNAs are easy to synthesize and deliver, miR-7 could be a potential therapeutic means to macrocephaly caused by Gli3-deficiency.