CREsted: modeling genomic and synthetic cell-type-specific enhancers across tissues and species
By onCREsted, a sequence-based deep learning model, analyzes genomic regulatory code, decodes enhancer grammar, and designs synthetic enhancers. It preprocesses single-cell data, models chromatin accessibility, and compares cell states across tissues.
A single Citrobacter rodentium infection in Pink1 knockout and wild type mice leads to regional blood-brain-barrier perturbation and limited microglial activation without dopamine neuron axon terminal loss
By onResearch suggests immune system activation may contribute to Parkinson’s disease development. Mild infections can increase BBB permeability, triggering brain inflammation in genetically susceptible individuals, potentially leading to PD pathology.
STING dampens the unfolded protein response to enable the presentation of self antigens on MHC-I during inflammation
By onSTING pathway regulates antigen presentation through the UPR, impacting immune response in PD and autoimmune diseases. Targeting STING and UPR could be therapeutic.
An LRRK2 variant blocks NCOA4 trafficking upon iron overload, leading to ferroptotic death
By onWe examined the impact of mutant LRRK2-G2019S on iron homeostasis within a model macrophage cell line. Results revealed a dysregulation of iron-related proteins in steady state and a complete block in the degradation of the ferritinophagy NCOA4.
Cryo-EM structure of soluble VPS13C suggests its regulation by a conformational switch and by calmodulin
By onStructural studies of the Parkinson's protein VPS13C provide a molecular basis for understanding its function and regulation.
Cell-autonomous and non-cell-autonomous drivers of dopamine neuron vulnerability in Parkinson’s disease
By onThis review examines evidence for cell-autonomous mechanisms and non-cell-autonomous processes arising from glial and peripheral immune cells and how these pathways can converge to create chronic cellular stress and trigger cell death mechanisms.
Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress
By onCryo-ET showed protein aggregates, altered cristae, and reduced ribosome complexes in stressed mitochondria. Mitochondrial Hsp60 undergoes conformational changes to aid in protein folding, shedding light on mitochondrial proteostasis mechanisms.
Excitatory synaptic structural abnormalities produced by templated aggregation of α-syn in the basolateral amygdala
By onPD and DLB involve α-syn inclusions in the amygdala affecting cognition and emotions. Cortico-amygdala synapses with α-syn aggregates show increased volume of synapses, potentially contributing to behavioral impairments.
Protocol for efficient CRISPRi-mediated silencing of retrotransposons in human pluripotent stem cells
By onThis methods paper outlines silencing transposable elements in hiPSCs using CRISPRi. Describes gRNA design, validation via multiome approach. Enables functional studies on TE transcription in hiPSC models.
Behavioral screening defines the molecular Parkinsonism-related subgroups in Drosophila
By onWe created a new collection of 24 genetically well-controlled Drosophila models of familial forms of parkinsonism. Using unbiased behavioral screening and machine learning we identified three clusters of mutants that converge.
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.
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.
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 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.
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.
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.
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.
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.
