A Novel α-Synuclein K58N Missense Variant in a Patient with Parkinson’s Disease
By on15% of cases of PD are linked to mutations in the SNCA gene. A novel K58N mutation in a patient showed typical PD symptoms, genetic testing, and biophysical studies revealing structural effects and abnormal cellular behavior of SNCA.
Leucine Rich Repeat Kinase 2: Pathways to Parkinson’s Disease
By onResearch on LRRK2 in Parkinson's disease has advanced, revealing how mutations activate the kinase, phosphorylate Rab proteins, disrupt cell functions like Hedgehog signaling, and contribute to the disease. LRRK2 inhibitors show promise for therapy.
Lipid dynamics at membrane contact sites
By onLipid building blocks in eukaryotes are mainly produced in the endoplasmic reticulum and moved to other organelles via vesicles or proteins at organelle contact sites. We review what is known.
LRRK2-mutant microglia and neuromelanin synergize to drive dopaminergic neurodegeneration in an iPSC-based Parkinson’s disease model
By onPD is a neurodegenerative disorder characterized by the loss of neuromelanin (NM)-containing dopamine neurons. This work highlights NM-activated microglia’s role in PD progression, and provides a model for testing therapeutic targets.
Adeno-associated viral vectors for modeling Parkinson’s disease in non-human primates
By onThe lack of adequate animal models of PD represents the main barrier to preclinical therapies to succeed in clinical trials. However, by novel generations of viral vectors coding for different forms of a-syn species and related genes.
Standardised TruAI Automated Quantification of Intracellular Neuromelanin Granules in Human Brain Tissue Sections
By onTo standardise and automate the quantitation of human-unique neuromelanin granules in catecholamine neurons in post-mortem tissue sections from healthy individuals at different ages to understand any changes in these granules with age.
Longitudinal neuromelanin changes in prodromal and early Parkinson’s disease in humans and rat model
By onResults in animals and humans show that neuromelanin-sensitive-MRI is a marker of the intracellular neuromelanin accumulation and then of neuronal degeneration and originates mainly from T1 reduction effect of neuromelanin.
LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons
By onPD LRRK2 influences the effects of haloperidol, a common antipsychotic, on striatal indirect pathway neurons. Inhibiting LRRK2 kinase activity reduces haloperidol’s motor side effects, suggesting a way to ease antipsychotic side effects.
GenoTools: an open-source Python package for efficient genotype data quality control and analysis
By onGenoTools, a Python package, streamlines population genetics research by integrating ancestry estimation, quality control, and genome-wide association studies capabilities into efficient pipelines. By tracking samples, variants, and quality-specific measures throughout fully customizable pipelines, users can easily manage genetics data for large and small studies. GenoTools' “Ancestry” module renders highly accurate predictions, allowing for high-quality ancestry-specific studies, and enables custom ancestry model training and serialization specified to the user's genotyping or sequencing platform. As the genotype processing engine that powers several large initiatives, including the NIH's Center for Alzheimer's and Related Dementias and the Global Parkinson's Genetics Program, GenoTools was used to process and analyze the UK Biobank and major Alzheimer's disease and Parkinson's disease datasets with over 400,000 genotypes from arrays and 5,000 whole genome sequencing samples and has led to novel discoveries in diverse populations. It has provided replicable ancestry predictions, implemented rigorous quality control, and conducted genetic ancestry-specific genome-wide association studies to identify systematic errors or biases through a single command. GenoTools is a customizable tool that enables users to efficiently analyze and scale genotyping and sequencing (whole genome sequencing and exome) data with reproducible and scalable ancestry, quality control, and genome-wide association studies pipelines.
Adult-specific Reelin expression alters striatal neuronal organization: implications for neuropsychiatric disorders
By onReelin levels might modulate the numbers of striatal interneurons and the density of the nigrostriatal dopaminergic projections, suggesting that these changes may be involved in the protection of Reelin against neuropsychiatric disorders.
A RAB7A Phosphoswitch Coordinates Rubicon Homology Protein Regulation of PINK1/Parkin-Dependent Mitophagy
By onPublished: Structural and functional data support a model in which the TBK1-dependent phosphorylation of RAB7A serves as a switch, promoting mitophagy by relieving Rubicon inhibition and favoring Pacer activation. View original preprint.
A data-driven single-cell and spatial transcriptomic map of the human prefrontal cortex
By onA data-driven molecular map of the DLPFC reveals distinct spatial domains and cell populations, offering insights into neuropsychiatric disorders. The study provides a roadmap for implementing spatial clustering approaches in the human brain.
Integrated multi-cohort analysis of the Parkinson’s disease gut metagenome
By onThe authors perform metagenomic sequencing of multiple geographically-disparate cohorts and find that stereotypic changes in the functional metabolic potential of the gut microbiome are a consistent feature of PD.
A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice
By onWhat should Parkinson's Disease patients eat? This study shows that dietary fiber impacts gut microbes and immune cells in the brain of a mouse model of Parkinson's.
Nicotine-Mediated Rescue of α-Synuclein Toxicity Requires Synaptic Vesicle Glycoprotein 2 in Drosophila
By onBackground: Parkinson's disease (PD) is characterized by α-synuclein aggregation and loss of dopamine neurons. Risk of PD arises due to a combination of genetic and environmental factors, which may interact, termed gene-environment (G×E) interactions. An inverse association between smoking and the risk of PD is well established, and a previous genome-wide G×E interaction study identified genetic variation in the synaptic-vesicle glycoprotein 2C (SV2C) locus as an important mediator of the degree to which smoking is inversely associated with PD. Objective: We sought to determine the mechanism of the smoking-SV2C interaction in a Drosophila model of PD. Methods: Flies expressing human α-synuclein in all neurons develop the hallmarks of PD, including motor dysfunction, loss of dopaminergic (DA) neurons, and formation of α-synuclein inclusions. We assessed the effects of increasing doses of nicotine on these parameters of neurodegeneration, in the presence or absence of knockdown of two Drosophila orthologues of SV2, hereafter referred to as SV2L1 and SV2L2. Results: The α-synuclein-expressing flies treated with nicotine had improved locomotion, DA neuron counts, and α-synuclein aggregation. However, in α-synuclein-expressing flies in which SV2L1 and SV2L2 were knocked down, nicotine failed to rescue neurodegeneration. Conclusions: This work confirms a G×E interaction between nicotine and SV2, defines a role for this interaction in α-synuclein proteostasis, and suggests that future clinical trials on nicotine should consider genetic variation in SV2C. Furthermore, this provides proof of concept that our model can be used for the mechanistic study of G×E, paving the way for the investigation of additional G×E interactions or the identification of novel G×E. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors
By onGain-of-function mutations in LRRK2 gene lead to by increasing phosphorylation of RAB GTPases. Over-phosphorylation of RAB3A disrupts synaptic vesicle transport in human neurons, altering synaptic protein distribution and likely contributing to PD.
The GBA variant E326K is associated with alpha-synuclein aggregation and lipid droplet accumulation in human cell lines
By onThe GBA variant E326K is associated with alpha-synuclein aggregation and lipid droplet accumulation in fibroblasts.
DOPA pheomelanin is increased in nigral neuromelanin of Parkinson’s disease
By onNeuromelanin in the substantia nigra may be a key factor contributing to dopaminergic neuron vulnerability in Parkinson’s disease. Here, the authors investigated the relative composition and specific roles of pheomelanin and eumelanin in PD.
Black and African American Connections to Parkinson’s Disease Study: Addressing Missing Diversity in Parkinson’s Disease Genetics
By onOur current understanding of Parkinson's disease and atypical parkinsonism-related syndromes is disproportionately based on studying populations of European ancestry, leading to a significant gap of knowledge concerning clinical features, genetics, and pathophysiology underlying disease etiology in underrepresented populations, including Black and African American individuals.
Multi-modality machine learning predicting Parkinson’s disease
By onPersonalized medicine promises individualized disease prediction and treatment. The convergence of machine learning (ML) and available multimodal data is key moving forward. We build upon previous work to deliver multimodal predictions of Parkinson’s disease (PD) risk and systematically develop a model using GenoML, an automated ML package, to make improved multi-omic predictions of PD, validated in an external cohort. We investigated top features, constructed hypothesis-free disease-relevant networks, and investigated drug–gene interactions. We performed automated ML on multimodal data from the Parkinson’s progression marker initiative (PPMI). After selecting the best performing algorithm, all PPMI data was used to tune the selected model. The model was validated in the Parkinson’s Disease Biomarker Program (PDBP) dataset. Our initial model showed an area under the curve (AUC) of 89.72% for the diagnosis of PD. The tuned model was then tested for validation on external data (PDBP, AUC 85.03%). Optimizing thresholds for classification increased the diagnosis prediction accuracy and other metrics. Finally, networks were built to identify gene communities specific to PD. Combining data modalities outperforms the single biomarker paradigm. UPSIT and PRS contributed most to the predictive power of the model, but the accuracy of these are supplemented by many smaller effect transcripts and risk SNPs. Our model is best suited to identifying large groups of individuals to monitor within a health registry or biobank to prioritize for further testing. This approach allows complex predictive models to be reproducible and accessible to the community, with the package, code, and results publicly available.
