A framework 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 three molecular Parkinsonism 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.
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.
Early deficits in an in vitro striatal microcircuit model carrying the Parkinson’s GBA-N370S mutation
By onThe results highlight the unique utility of modeling striatal neurons in a modular and highly physiological circuit, which is essential to reveal mechanistic insights of the loss of electrical functional integrity in the striata of GBA1 PD patients.
Scientific Perspectives: Structural Biology of LRRK2 and its Interaction with Microtubules
By onMutations in LRRK2 are linked to Parkinson's disease. LRRK2 regulates membrane trafficking and interacts with microtubules. Recent studies have revealed its cytosolic and microtubule-bound forms using cryo-EM and cryo-ET techniques.
Role of autophagy pathway in Parkinson’s disease and related Genetic Neurological disorders
By onThe authors provide a comprehensive overview of the general importance of autophagy in Parkinson’s disease (PD) and related disorders of the central nervous system (CNS).
Scalable, flexible carbon fiber electrode thread arrays for three-dimensional probing of neurochemical activity in deep brain structures of rodents
By onThe authors' CFET array has the potential to unlock a wide range of applications, from uncovering the role of neuromodulators in synaptic plasticity, to addressing safety barriers in clinical translation toward diagnostic and adaptive treatment in PD
Mechanisms Controlling Selective Elimination of Damaged Lysosomes
By onLysophagy, triggered by membrane rupture, involves galectins binding to lysosomal contents to promote autophagic recycling. Damaged lysosomes are ubiquitylated, leading to autophagosome formation for degradation in healthy lysosomes.
Impact of the dopamine system on long-term cognitive impairment in Parkinson disease: an exploratory study
By onBackground Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD). Using data from a multi-site, international, prospective cohort study, authors explored the impact of dopamine system-related biomarkers on CI in PD. The study provides preliminary evidence that alterations in the dopamine system predict the development of clinically-relevant, cognitive impairment in Parkinson's disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course.
Vesicular dysfunction and pathways to neurodegeneration
By onIn this review, the pathways that have emerged as critical for neuronal survival in the human brain are discussed, illustrating the diversity of proteins and cellular events with three molecular case studies from different neurological diseases.
