Sunlight-mediated removal of endocrine disruptors from wastewater using trimetallic core-shell Ag-TeO2@ZnO nanocomposites.

The current work emphasizes the preparation of trimetallic core-shell Ag-TeO2@ZnO nanocomposites (NCs) by thermo-mechanical method for the efficient photocatalytic degradation of 2,4-Dichlorophenol and ß-naphthol pollutants. FE-SEM shows that Ag and TeO2nanoparticles are deposited on the surface of ZnO nanotubes. The band gap of pristine ZnO NPs and 5 wt% Ag-TeO2@ZnO nanocomposites are found to be 3.16 and 2.96 eV, respectively. The calculated specific surface area (SBET) of pristine ZnO NPs and 5 wt% Ag-TeO2@ZnO nanocomposites are 40.47 and 45.66 m2g-1respectively, confirming that Ag and TeO2nanoparticles contribute to increasing in surface area of pure ZnO. The synthesised nanocomposite showed excellent photocatalytic performance for the degradation of ß -naphthol (95.6%) in 40 min at the concentration of (0.6 mg ml-1) and 2,4-DCP (99.6%) in 180 min (0.4 mg ml-1) under natural sunlight. Cyclic Voltammetry and Electrochemical Impedance Spectroscopy were carried out to study the electrochemical properties. The determination of reactive oxygen species (ROS) confirmed that the degradation of the pollutants by 5 wt% Ag-TeO2@ZnO NCs was due to the formation of superoxide radicals. Electron paramagnetic resonance revealed the presence of sharp signals in pure ZnO nanoparticles at g ∼1.95 and oxygen vacancy peak at g ∼2.01 in 5 wt% Ag-TeO2@ZnO NCs. To study the mechanism behind the degradation of pollutants, Scavenger test using histidine and ascorbic acid (ROS scavengers) was performed. The synthesised nanocomposites are highly stable and showed enhanced efficiency up to three cycles, confirming their reusability as a photocatalyst.

Oxidative Coupling and Self-Assembly of Polyphenols for the Development of Novel Biomaterials.

In recent years, the development of biomaterials from green organic sources with nontoxicity and hyposensitivity has been explored for a wide array of biotherapeutic applications. Polyphenolic compounds have unique structural features, and self-assembly by oxidative coupling allows molecular species to rearrange into complex biomaterial that can be used for multiple applications. Self-assembled polyphenolic structures, such as hollow spheres, can be designed to respond to various chemical and physical stimuli that can release therapeutic drugs smartly. The self-assembled metallic-phenol network (MPN) has been used for modulating interfacial properties and designing biomaterials, and there are several advantages and challenges associated with such biomaterials. This review comprehensively summarizes current challenges and prospects of self-assembled polyphenolic hollow spheres and MPN coatings and self-assembly for biomedical applications.

Polygenic Risk Scores Validated in Patient-Derived Cells Stratify for Mitochondrial Subtypes of Parkinson's Disease.

OBJECTIVE: The aim of our study is to better understand the genetic architecture and pathological mechanisms underlying neurodegeneration in idiopathic Parkinson's disease (iPD). We hypothesized that a fraction of iPD patients may harbor a combination of common variants in nuclear-encoded mitochondrial genes ultimately resulting in neurodegeneration. METHODS: We used mitochondria-specific polygenic risk scores (mitoPRSs) and created pathway-specific mitoPRSs using genotype data from different iPD case-control datasets worldwide, including the Luxembourg Parkinson's Study (412 iPD patients and 576 healthy controls) and COURAGE-PD cohorts (7,270 iPD cases and 6,819 healthy controls). Cellular models from individuals stratified according to the most significant mitoPRS were subsequently used to characterize different aspects of mitochondrial function. RESULTS: Common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk in independent cohorts (Luxembourg Parkinson's Study odds ratio, OR = 1.31[1.14-1.50], p-value = 5.4e-04; COURAGE-PD OR = 1.23[1.18-1.27], p-value = 1.5e-29). Functional analyses in fibroblasts and induced pluripotent stem cells-derived neuronal progenitors revealed significant differences in mitochondrial respiration between iPD patients with high or low OXPHOS-PRS (p-values < 0.05). Clinically, iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients (false discovery rate [FDR]-adj p-value = 0.015), similar to prototypic monogenic forms of PD. Finally, iPD patients with high OXPHOS-PRS responded more effectively to treatment with mitochondrially active ursodeoxycholic acid. INTERPRETATION: OXPHOS-PRS may provide a precision medicine tool to stratify iPD patients into a pathogenic subgroup genetically defined by specific mitochondrial impairment, making these individuals eligible for future intelligent clinical trial designs. ANN NEUROL 2024;96:133-149.

Hyposalivation in patients with psoriasis: Association with severity, inflammatory, and anti-inflammatory cytokine biomarkers of the disease.

The aim of the study is to expound the effect of psoriasis on salivary glands by evaluating the secretion of saliva and salivary cytokine biomarkers in patients with psoriasis. This study was conducted by recruiting 120 subjects that included 60 patients diagnosed clinically with active psoriasis and 60 healthy controls who were age and gender matched to psoriatic subjects. Unstimulated whole saliva was collected from all the subjects by spitting method, and levels of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin-2 (IL-2), and IL-10 (IL-10) were determined via enzyme-linked immunosorbent assay (BT Lab, Shanghai, China). Secretion of saliva in psoriasis patients was considerably reduced than in healthy controls. The concentrations of pro-inflammatory cytokines (TNF-α, IFN-γ, and IL-2) were significantly increased, whereas level of anti-inflammatory cytokine (IL-10) was markedly decreased in the saliva of psoriasis patients with hyposalivation compared to healthy subjects. Our results demonstrated significant negative correlation of salivary flow rates with the disease severity. No significant correlations were obtained between salivary levels of tested cytokines and salivary flow rates in our study. Findings of the study reflect inflammation of salivary glands with reduced salivary flow rates in psoriasis patients. The inflammatory responses in salivary gland tissues by virtue of increased pro-inflammatory cytokines concentrations together with lower anti-inflammatory cytokine levels may have a role in affecting the saliva secretion in psoriasis patients. Secretion of unstimulated saliva in psoriasis patients decreases with the severity and duration of the disease.

Resequencing the complete SNCA locus in Indian patients with Parkinson's disease.

The genetic loci implicated in familial Parkinson's disease (PD) have limited generalizability to the Indian PD population. We tested mutations and the frequency of known mutations in the SNCA gene in a PD cohort from India. We selected 298 PD cases and 301 age-matched controls for targeted resequencing (before QC), along with 363 PD genomes of Indian ancestry and 1029 publicly available whole genomes from India as healthy controls (IndiGenomes), to determine the frequency of monogenic SNCA mutations. The raw sequence reads were analyzed using an in-house analysis pipeline, allowing the detection of small variants and structural variants using Manta. The in-depth analysis of the SNCA locus did not identify missense or structural variants, including previously identified SNCA mutations, in the Indian population. The familial forms of SNCA gene variants do not play a major role in the Indian PD population and this warrants further research in the under-represented population.

Synthesis and biological properties of novel glucose-based fluoro segmented macromolecular architectures.

The emergence of novel well-defined biological macromolecular architectures containing fluorine moieties displaying superior functionalities can satisfactorily address many biomedical challenges. In this research, ABA- and AB-type glucose-based biological macromolecules were synthesized using acryl-2,3,4,6-tetra-O-acetyl-D-glucopyranoside with pentafluorophenyl (FPM), pentafluorobenzyl (FBM), phenyl (PM) and benzyl (BM) methacrylate-based macro-RAFT agents following RAFT polymerization. The macro-RAFT agents and the corresponding copolymers were characterized by 19F, 1H, and 13C NMR and FTIR spectroscopic techniques to understand the chemical structure, molecular weight by size-exclusion chromatography, thermal analysis by TGA and DSC. Thermal stability (Td5%) of the FPM and FBM fluoro-based polymers was observed in the range of 219-267 °C, while the non-fluoro PM and BM polymers exhibited in the range of 216-264 °C. Among the macro-RAFT agents, PFPM (107 °C, ΔH: 0.613 J/g) and PPM (103 °C, ΔH: 0.455 J/g) showed higher Tm values, while among the block copolymers, PFBM-b-PG (123 °C, ΔH: 0.412 J/g) and PG-b-PFPM-b-PG (126 °C, ΔH: 0.525 J/g) exhibited higher Tm values. PFBMT and PPM macro-RAFT agents, PPM-b-PG and PG-b-PPM-b-PG copolymer spin-coated films showed the highest hydrophobicity (120°) among the synthesized polymers. The block copolymers exhibited self-assembled segregation by using relatively hydrophobic segments as the core and hydrophilic moieties as the corona. Synthesized biological macromolecules exhibit maximum antibacterial activity towards S. aureus than E. coli bacteria. Fluorophenyl (PFPM) and non-fluorobenzyl-based (PBMT) macro-RAFT agents exhibit low IC50 values, suggesting high cytotoxicity. All the triblock copolymers exhibit lesser cytotoxicity than the di-block polymers.

Human iPSC 4R tauopathy model uncovers modifiers of tau propagation.

Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer's Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.

RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses.

BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease. METHODS: We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities. FINDINGS: Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71. INTERPRETATION: RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling. FUNDING: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

A Novel PINK1 p.F385S Loss-of-Function Mutation in an Indian Family with Parkinson's Disease.

BACKGROUND: Most Parkinson's disease (PD) loci have shown low prevalence in the Indian population, highlighting the need for further research. OBJECTIVE: The aim of this study was to characterize a novel phosphatase tensin homolog-induced serine/threonine kinase 1 (PINK1) mutation causing PD in an Indian family. METHODS: Exome sequencing of a well-characterized Indian family with PD. A novel PINK1 mutation was studied by in silico modeling using AlphaFold2, expression of mutant PINK1 in human cells depleted of functional endogenous PINK1, followed by quantitative image analysis and biochemical assessment. RESULTS: We identified a homozygous chr1:20648535-20648535 T>C on GRCh38 (p.F385S) mutation in exon 6 of PINK1, which was absent in 1029 genomes from India and in other known databases. PINK1 F385S lies within the highly conserved DFG motif, destabilizes its active state, and impairs phosphorylation of ubiquitin at serine 65 and proper engagement of parkin upon mitochondrial depolarization. CONCLUSIONS: We characterized a novel nonconservative mutation in the DFG motif of PINK1, which causes loss of its ubiquitin kinase activity and inhibition of mitophagy. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Exploring the Potential Benefits of Bovine Colostrum Supplementation in the Management of Diabetes and Its Complications: A Comprehensive Review.

Diabetes is a metabolic illness marked by elevated levels of glucose in the bloodstream due to the inadequate production or use of insulin in the body. Diabetes can result in a range of consequences, with the most prevalent being cardiovascular disease, renal failure, vision loss, and limb removal. Natural compounds isolated from different sources, like colostrum, are the most important compounds for the treatment of diabetes. Colostrum is a form of lactation produced by mammals in the first days after giving birth to their offspring, having a rich source of constituents and showing multipharmacological properties. This review was prepared on the basis of a variety of authoritative search databases, including Google Scholar, Scopus, and PubMed. In addition, the publications and other online sources were also included. In the literature search, the terms "colostrum," "diabetes," "uses," "management," "constituent," "composition," "alternative sources," "mechanism of action," "preclinical," "clinical," "marketed formulations," and "patents" were utilized as keywords and collected from last two decades. Colostrum has been utilized as a treatment for a wide variety of illnesses due to its active constituents. A variety of colostrums are available in the market, like goat colostrum, porcine colostrum, sheep colostrum, human colostrum and many more. They have the full potential of nutrients like minerals, vitamins, lactose, essential enzymes, proteins and high concentrations of immunoproteins. Mostly, the colostrums are used for treating diabetes and its complications. Preclinical and clinical studies of metabolic syndrome, especially on diabetes and its complications, were also reported at the National and International levels, which evidently prove that the use of colostrums in the long term can be beneficial for various ailments associated with diabetes. In general, the findings of this review indicate that supplementation with colostrum may hold promise as a novel therapeutic intervention for people who have diabetes and its complications; however, additional research is required to fully understand its mechanisms of action and determine the best possible dosage as well as the time period of supplementation.

A Case of Posterior Cortical Atrophy Presenting with Mood and Psychotic Symptoms.

Posterior cortical atrophy (PCA) is a rare neurodegenerative disorder characterized by predominant visual deficits due to its atrophy of the occipital lobes. Patients typically have preserved cognitive function during the early stages, making diagnosis more difficult when compared to other neurocognitive disorders. In this case, the patient presented predominantly with mood symptoms, delusions, and visual hallucinations. The disease course began 5 years ago with anxiety and insomnia. It developed into depressive symptoms including two suicide attempts (SAs), paranoia, and hallucinations. The diagnosis was eventually reached utilizing a thorough clinical exam, neuropsychological testing, MRI, positron emission tomography (PET), and dopamine transporter (DAT) scans. We conclude that mood or psychotic symptoms that emerge, escalate, or change dramatically at later ages merit further workup to evaluate for underlying neurodegenerative disorders.

Transfersomes: Recent Advances, Mechanisms, Exhaustive Applications, Clinical Trials, and Patents

A feasible nano transdermal delivery system generally intends to have specific ideal and distinct characteristics primarily for safety, clinical efficacy, and boosted therapeutic index. The delivery of drugs, particularly macromolecules, across the skin is one of the most strenuous obstacles in front of pharmaceutical scientists. Technology advancement has provided some opportunities to overcome this difficulty by utilising microneedle arrays, ablation, laser methods etc. However, associated uneasiness, painful sensation, and higher cost of therapies limit their day-to-day use. Therefore, researchers have focused on developing alternate carriers like ultra-deformable liposomes, also termed transfersomes. Transfersomes are composed of a lipid bilayer containing phospholipids and an edge activator to facilitate drug delivery via transdermal route to deeper layers of skin and for higher systemic bioavailability. The bilayer structure of transfersomes allows ease of encapsulation of both hydrophilic and lipophilic drugs with higher permeability than typical liposomes. Therefore, among various vesicular systems, transfersomes have developed much interest in targeted and sustained drug delivery. The current review primarily emphasizes critical aspects of transfersomes, including their applications, clinical trial studies, and patents found in various literature sources.

Disease-linked mutations in Munc18-1 deplete synaptic Doc2.

Heterozygous de novo mutations in the neuronal protein Munc18-1/STXBP1 cause syndromic neurological symptoms, including severe epilepsy, intellectual disability, developmental delay, ataxia and tremor, summarized as STXBP1 encephalopathies. Although haploinsufficiency is the prevailing disease mechanism, it remains unclear how the reduction in Munc18-1 levels causes synaptic dysfunction in disease as well as how haploinsufficiency alone can account for the significant heterogeneity among patients in terms of the presence, onset and severity of different symptoms. Using biochemical and cell biological readouts on mouse brains, cultured mouse neurons and heterologous cells, we found that the synaptic Munc18-1 interactors Doc2A and Doc2B are unstable in the absence of Munc18-1 and aggregate in the presence of disease-causing Munc18-1 mutants. In haploinsufficiency-mimicking heterozygous knockout neurons, we found a reduction in Doc2A/B levels that is further aggravated by the presence of the disease-causing Munc18-1 mutation G544D as well as an impairment in Doc2A/B synaptic targeting in both genotypes. We also demonstrated that overexpression of Doc2A/B partially rescues synaptic dysfunction in heterozygous knockout neurons but not heterozygous knockout neurons expressing G544D Munc18-1. Our data demonstrate that STXBP1 encephalopathies are not only characterized by the dysfunction of Munc18-1 but also by the dysfunction of the Munc18-1 binding partners Doc2A and Doc2B, and that this dysfunction is exacerbated by the presence of a Munc18-1 missense mutant. These findings may offer a novel explanation for the significant heterogeneity in symptoms observed among STXBP1 encephalopathy patients.

Insights into Prospects of Novel NSAID Prodrugs in the Management of Gastrointestinal Toxicity: A Perspective Review.

Non-steroidal anti-inflammatory drugs (NSAIDs) have a long history in the healthcare system due to their therapeutic potential. These NSAIDs cause ulcerogenicity, stomach pains, gastrointestinal hemorrhage, mucosa bleeding, and pancreatitis when used moderately and consistently. With researchers, managing the aforementioned adverse effects therapeutically is getting increasingly difficult. One method for creating NSAID moieties with low penetration as well as ulcerogenic properties is the prodrug technique. During the oral consumption of NSAID-prodrugs, ulcerations, intestinal hemorrhage, and mucosa hemorrhage have significantly decreased. Considering this background, this review focussed on NSAID prodrugs as well as their justifications, the pathogenesis of NSAIDs inducing gastrointestinal toxicity, and the role of different antioxidants and spacer groups. Prodrug moieties have more advantages over parent medicines concerning both solubility and lipophilicity. In general, NSAID-class prodrugs can successfully treat both acute and long-term inflammation and aches without causing ulcerotoxicity and related gastrointestinal side effects, which reduces their burden from the pharmacoeconomic perspective.

An international comparative policy analysis of opioid use disorder treatment in primary care across nine high-income jurisdictions.

BACKGROUND: Opioid use disorder (OUD) and opioid-related harms are current health priorities in many high-income countries such as Canada. Opioid agonist therapy (OAT) is an effective evidence-based treatment for OUD, but access is often limited. AIMS: To describe and compare OUD treatment policies across nine international jurisdictions, and to understand how they are situated within their primary care and health systems. METHODS: Using policy documents, we collected data on health systems, drug use epidemiology, drug policies, and OUD treatment from Australia, Canada, France, Germany, Ireland, Portugal, Sweden, Switzerland, and Taiwan. We used the health system dynamics framework and adapted definitions of low- and high-threshold treatment to describe and compare OUD treatment policies, and to understand how they may be shaped by their health systems context. RESULTS: Broad similarities across jurisdictions included the OAT pharmacological agents used and the need for supervised dosing; however, preferred OAT, treatment settings, primary care and specialist physicians' roles, and funding varied. Most jurisdictions had elements of lower-threshold treatment access, such as the availability of treatment through primary care and multiple OAT options, but the higher-threshold criteria of supervised dosing. CONCLUSIONS: From the Canadian perspective, there are opportunities to improve accessibility of OUD care by drawing on how different jurisdictions incorporate multidisciplinary care, regulate OAT medications, remunerate healthcare professionals, and provide funding for services.

A pathogenic variant in RAB32 causes autosomal dominant Parkinson's disease and activates LRRK2 kinase.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD. Methods: Affected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed. Findings: We found RAB32 c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families. RAB32 Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably, RAB32 Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase. Interpretation: Our study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD. Funding: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J. Fox Foundation for Parkinson's Research, and the UK Medical Research Council.