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Objective: Aquaporin-4 (AQP4) facilitates a sleep-enhanced interstitial brain waste clearance system. This study was conducted to determine the clinical implication of AQP4 polymorphisms in Parkinson's disease (PD). Methods: Three-hundred and eighty-two patients with PD and 180 healthy controls with a mean follow-up time of 66.1 months from the Parkinson's Progression Marker Initiative study were analyzed. We examined whether AQP4 SNPs were associated with an altered rate of motor or cognitive decline using linear mixed model and Cox regression. We then investigated whether AQP4 SNPs were associated with Aβ burden as measured by 18F Florbetapir standard uptake values. Furthermore, we examined if AQP4 SNPs moderated the association between REM sleep behavior disorder (RBD) and CSF biomarkers. Results: In patients with PD, AQP4 rs162009 (AA/AG vs. GG) was associated with slower dementia conversion, better performance in letter-number sequencing and symbol digit modalities, lower Aβ deposition in the putamen, anterior cingulum, and frontotemporal areas. In the subgroup of high RBD screening questionnaire score, rs162009 AA/AG had a higher CSF Aβ42 level. rs162009 AA/AG also had better performance in semantic fluency in healthy controls. Besides, rs68006382 (GG/GA vs. AA) was associated with faster progression to mild cognitive impairment, worse performance in letter-number sequencing, semantic fluency, and symbol digit modalities in patients with PD. Interpretation: Genetic variations of AQP4 and subsequent alterations of glymphatic efficacy might contribute to an altered rate of cognitive decline in PD. AQP4 rs162009 is likely a novel genetic prognostic marker of glymphatic function and cognitive decline in PD. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that genetic factors play a key role in the development of Parkinson's disease (PD). The variant rs11240572 in the PARK16 gene locus is strongly associated with PD. However, its effect on the pathogenesis of PD is yet to be clarified. The objective of the study was to explore the effect of the PARK16 rs11240572 variant on brain structure in PD patients. A total of 51 PD patients were enrolled in the study and genotyped for the rs11240572 variant. Clinical assessments and MRI scans were conducted across all participants. Voxel-based morphometry (VBM) was used to investigate gray matter volume (GMV) of the whole brain between these two groups. Correlation analysis was performed to identify the relationships between GMV and clinical features. There were 17 rs11240572-A variant carriers and 34 non-carriers, with no significant demographic differences between these two groups. Compared with non-carriers, rs11240572-A carriers showed increased GMV in the left caudate nucleus and putamen, but decreased GMV in the left superior temporal gyrus and supramarginal gyrus. In non-carriers, left basal ganglia GMV was positively correlated with UPDRS III (r = 0.365, p = 0.034) and bradykinesia (r = 0.352, p = 0.042), but negatively correlated with MMSE (r = – 0.344, p = 0.047), while in carriers negative correlation between basal ganglia GMV and MMSE was also observed (r = – 0.666, p = 0.004). Moreover, the GMV of left temporoparietal cortex was positively associated with cognitive function in both groups (carriers, r = 0.692, p = 0.002; non-carriers, r = 0.879, p < 0.001). When reducing the sample size of non-carriers to the level of the carrier sample, similar correlations were observed in both groups. Our study showed that the PARK16 rs11240572 variant affects the brain structure of patients with PD, especially in the basal ganglia and temporoparietal cortex. This indicated that this variant might play an important role in the pathogenesis of PD. [ABSTRACT FROM AUTHOR]

• Parkin reduces the efficiency of human fibroblasts reprogramming neurons. • Parkin -mutation reduces the complexity of neurites in induced neurons. • The parkin mutation hinds the maturation of induced neurons. Parkinson's disease (PD) is one of the most common neurodegenerative disorders, and mainly characterized by the progressive degeneration of dopaminergic (DA) neurons in the midbrain substantia nigra and non-DA neurons in many other parts of the brain. Previous studies have shown that several genes associated with the causes of PD can influence neurite outgrowth. Mutations of PRKN (encoding parkin, an E3 ubiquitin ligase) are the most frequent cause of recessively inherited PD. The lack of a PD phenotype in Prkn -knockout mice may imply a unique vulnerability of neurons to parkin mutations. CRISPR/Cas9 technology was used to target random mutations into exon3 of PRKN in human fibroblasts cell line MRC-5. The induced DA neurons were achieved from direct conversion of fibroblasts (with or without PRKN mutations) via a cocktail of transcriptional factors (Ascl1, Nurr1, Lmx1a, miRNA124, p53 shRNA) and chemicals (CHIR99021, Purmorphamine, TGFβ3, BDNF, GDNF, NGF and Y27632). Herein, we successfully established human neuronal cell models with parkin mutations from fibroblast-reprogrammed neurons. In these neurons, not only were the induced ratio and number of mature neurons markedly decreased, but also the complexity of the neuronal processes, measured by total neurite length and number of terminals, was greatly reduced, in TH+ and TH−neurons with PRKN mutations. The results suggest that parkin not only maintains the morphological complexity of human neurons, but also influences maturation and differentiation in the fibroblast reprogramming process. [ABSTRACT FROM AUTHOR]

[Display omitted] • We first replicated the effects of 38 novel GWAS-identified PD-related Loci in a Chinese population. • The rs2248244 of DYRK1A was a risk factor for sporadic PD in our study. • The rs11610045 of FBRSL1 and rs76116224 of KCNS3 have protective effects on sporadic PD. • We built GWAS-derived PRS models which had predictive value for PD risk in the Chinese population. Recently, a meta-analysis of genome-wide association studies (GWASs) has identified 38 novel independent loci associated with risk of Parkinson's disease (PD) in European populations. We sought to investigate whether these genetic susceptibility variants could be replicated in the Chinese Han population. We genotyped 38 independent loci in 495 Chinese sporadic PD patients and 470 unrelated controls and performed allelic and genotypic association test using chi-square tests or Armitage test for trend. Polygenic risk score (PRS) models were built to evaluate the cumulative effects of the selected SNPs. We found that the rs11610045 of FBRSL1 (p = 0.02, OR = 0.63, allele model), rs76116224 of KCNS3 (p < 0.01, OR = 0.09, allele model), and the rs2248244 of DYRK1A (p = 0.02, OR = 1.35, allele model) were significantly associated with PD. The PRS model of cumulative effects of the SNPs associated with PD in our study had the area under the curve (AUC) of 0.61. Our study revealed that rs11610045 of FBRSL1 , rs76116224 of KCNS3 and rs2248244 of DYRK1A showed an impact on the risk of PD, and the GWAS-derived PRS models we built had predictive value for PD risk in the Chinese population. Further studies are needed to explore the pathogenesis of these potentially risk-associated variants. [ABSTRACT FROM AUTHOR]

• Tested 20 novel PD risk loci identified by GWAS in East Asian samples. • Allele of LRRK2 and IL1R2 have a higher risk of PD. • Genotypic models of ZNF184, PARK16, ITPKB significantly associated with PD. Genetic factors may play important roles in the pathogenesis of Parkinson's disease, and more than 40 loci involved in Parkinson's disease have been identified. Due to differing allele frequencies across origins, the associations of these loci and sporadic Parkinson's disease in the Eastern Chinese population are still unclear. The aim of this study was to investigate the relationship between 20 single nucleotide polymorphisms and Parkinson's disease in the Eastern Chinese population. A total of 441 Parkinson's disease patients and 384 healthy controls were recruited. The MassARRAY System was used to detect 20 single nucleotide polymorphisms. Odds ratios (OR) were calculated to assess the relationship between polymorphisms and Parkinson's disease susceptibility. We found that ITPKB rs4653767 (OR [95 % confidential interval (CI)] = 0.524 [0.309−0.922], p = 0.023), ZNF184 rs9468199 (OR [95 % CI] = 0.530 [0.326−0.862], p = 0.010), IL1R2 rs34043159 (OR [95 % CI] = 0.794 [0.651−0.968], p = 0.022), LRRK2 rs76904798 (OR [95 % CI] = 0.397 [0.225−0.700], p = 0.001), and PARK16 rs11240572 (OR [95 % CI] = 0.715 [0.531−0.962], p = 0.027) were significantly associated with Parkinson's disease. LRRK2 rs76904798, ZNF184 rs9468199, PARK16 rs11240572, ITPKB rs4653767, and IL1R2 rs34043159 may associate with Parkinson's disease in the Eastern Han Chinese population. [ABSTRACT FROM AUTHOR]