The IPDGC/GP2 Hackathon – an open science event for training in data science, genomics, and collaboration using Parkinson’s disease dataon
Op-Ed: The authors outline the projects and results arising from the international ‘hackathon’, which was a 3-day collaborative event between the Global Parkinson’s Genetics Program (GP2) and the International Parkinson’s Disease Genomics Consortium (IPDGC).
Dystonia-Parkinsonism Gene Variants in Individuals with Parkinsonism and Brain Scans without Evidence for Dopaminergic Deficit (SWEDD)on
Preprint: The authors aimed to investigate the genetic etiology of dystonia-parkinsonism through examining individuals with DAT SPECT scans without evidence of dopamine defects (SWEDD). They found pathogenic variants in parkinsonian-dystonia genes occurred in more than 10% of SWEDD individuals.
This review provides an overview of research involving PD genetics in under-represented populations, setting a baseline to measure future impact. The authors found a significant lack of population diversity in PD research, highlighting the need for more representation. This is a preprint.
Published: The authors performed automated machine learning on multi-modal data from PPMI and validated in the PDBP dataset. Further, they built networks to identify gene communities specific to PD. The model they built can improve multi-omic predictions of PD and improves disease risk prediction. View original preprint.
Published: The authors built a model of the primary sensory cortex (S1) in NetPyNE, using the data in the Neocortical Microcircuit Collaboration Portal. NetPyNE will make the S1 model more accessible and simpler to scale. View original preprint.
Multiscale model of primary motor cortex circuits predicts in vivo cell type-specific, behavioral state-dependent dynamicson
Published: The authors developed a biophysically detailed multiscale model of mouse primary motor cortex (M1) with over 10,000 neurons and 30 million synapses. The model accurately predicted in vivo layer- and cell type-specific responses (firing rates and LFP) associated with behavioral states and experimental manipulations (noradrenaline receptor blocking and thalamus inactivation).
Published: T cells have been shown to be overactive in individuals with PD. The authors tested a wide variety of commonly encountered immune targets on PD and non-PD control derived T cells and observed no differences between their immune responses. View original preprint.
Transcriptional analysis of peripheral memory T cells reveals Parkinson’s disease-specific gene signatureson
Published: Recent findings identified PD-associated autoimmune features. Using RNA sequencing, the authors found a broad gene expression profile in memory T cells and a specific PD-associated gene signature. Slpha-synuclein responding T cell gene expression profiles were associated with dysregulation in multiple cellular pathways related to PD genes. View original preprint.
Preprint: Decreasing alpha-synuclein levels is a potential therapeutic approach for synuleinopathies. The authors identified CDK14 regulates alpha-synuclein and show reduction of CDK14 in two different PD mouse models reduces alpha-synuclein and PD-like characteristics. They also demonstrate that inhibiting CDK14 with a drug lowers alpha-synuclein burdens in rodent and human neurons.
Preprint: The authors examine that relationship between PD and the environment by holistically characterizing environmental, health, and pharmacological traits associated with PD patients. They found numerous traits that were positively and negatively associated with PD.
The activities of LRRK2 and GCase are positively correlated in clinical biospecimens and experimental models of Parkinson’s diseaseon
Recent work suggests that LRRK2 kinase activity can modulate glucocerebrosidase (GCase) function. The authors investigated the relationship between LRRK2 and GBA1 by assessing GCase activity and found a positive correlation between the activities of LRRK2 and GCase in different cellular and ex vivo models. This is a preprint.
Published: Genetically engineered human pluripotent stem cells (hPSCs) containing specific mutations are invaluable for assessing the impact of gene mutations on disease pathology. The authors generated mutated hPSCs through utilization of a novel prime editing-based genome editing platform. Additionally, they show that our system can correct a known Parkinson’s disease-associated mutation. View original preprint here.
Preprint: LRRK2 mutations are a common cause of familial PD. In some circumstances, LRRK2 co-localizes with microtubules. The authors report a cryo-electron microscopy structure of the catalytic half of LRRK2, containing its kinase (closed conformation) and GTPase domains, bound to microtubules. Further, they identified amino acids that mediate microtubule binding.
Preprint: During autophagy initiation, the curved phagophore is stabilized. Using in vitro reconstitution, the authors show that WIPI2 and ATG16L1 bind these curved phagophores, WIPI2 binding directs membrane recruitment, and the ATG12-5-16L1 complex is responsible for membrane curvature.
Preprint: A hallmark of PD is the failure of quality control mechanisms in the cell, such as autophagy. The authors combined cell biology with correlative cryo-electron tomography in yeast cells to show a high resolution stepwise structural progression of autophagosome biogenesis. Further, they revealed the organelle interactome for growing autophagosomes.
Preprint: Protein aggregates, like tau, are associated with neurodegenerative diseases. Of interest is the cellular mechanism by which protein aggregates are removed. The authors show that the AAA+ chaperone, VCP, is recruited to ubiquitylated Tau, resulting in disaggregation. This finding identifies a role for VCP, Hsp70, and the ubiquitin-proteasome system.
Early Endosome Capture Proteomics and its Application to Amyloid Precursor Protein Intramembrane Processing by β and γ-Secretaseson
Preprint: The authors developed an assay, Endo-IP, to rapidly isolate early and sorting endosomes. Using this method, they found a unique proteomic landscape of early/sorting endosomes, distinct from lysosomal proteomic landscape. Combining Endo-IP and Lyso-IP, the authors provided a spatial digital snapshot of amyloid-beta products.
ggtranscript: an R package for the visualization and interpretation of transcript isoforms using ggplot2on
Published: Parkinson's disease likely reflects a complex interaction among genetic and environmental factors. Here, the role of nicotine, SV2 and the alpha-synuclein were examined. The study suggests that SV2 may be needed for the protection nicotine provides from Parkinson's-related neurotoxicity. View original preprint.
Preprint: Analysis of local genetic correlations can identify genomic regions that associate with more than one trait which can provide a better mechanistic understanding of disease. The authors identified several local genetic correlations between common neurodegenerative and neuropsychiatric diseases.
Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at Chr16q11.2 and on the MAPT H1 alleleon
Published: Genome-wide association studies have increased our understanding of PD by identifying genetic variants. The authors used a mitophagy screening assay to evaluate the functional significance of these variants and found two new regulators of PINK-dependent mitophagy, KAT8, and KANSL1. View original preprint.