Constitutive nuclear accumulation of endogenous alpha-synuclein in mice causes motor impairment and cortical dysfunction, independent of protein aggregation
By taliag onPublished: Nuclear alpha-synuclein may play a role in the pathogenesis of PD. To study this, the authors engineered SncaNLS mice that exhibit endogenous alpha-synuclein in the nucleus. After behavioral, histological, and biochemical analysis of the mice, the authors found that chronic nuclear alpha-synuclein can create toxic cellular phenotypes, independent of aggregation.
Reconstitution of cargo-induced LC3 lipidation in mammalian selective autophagy
By Blythe Lloyd onPublished: Selective autophagy is essential for maintaining cellular homeostasis. Using in vitro reconstitution, the authors explored the details of mitophagy initiation from autophagy receptor engagement through LC3 lipidation. They found that the core machinery engaged during mitophagy depends on different autophagy receptors, but LC3 lipidation is a universal feature. View original preprint.
ALS- and FTD-associated missense mutations in TBK1 differentially disrupt mitophagy
By Blythe Lloyd onPublished: TBK1 mutations are linked to neurodegenerative disorders. The authors explored how TBK1 functions in PINK1/Parkin-dependent mitophagy and how mutations lead to disease. TBK1 recruitment and kinase activity contributed to the clearance of damaged mitochondria (mitophagy). Further, they showed that TBK1 presence alone could disrupt the mitochondrial network. View original preprint.
Chemically induced senescence in human stem cell‐derived neurons promotes phenotypic presentation of neurodegeneration
By taliag onPublished: Using embryonic stem-cell derived neurons to model age-related neurodegenerative diseases is inherently difficult. The authors thereby developed a chemical cocktail to induce cellular senescence (without causing DNA damage), thereby inducing embryonic cells to exhibit features characteristic of aged cells. The cocktail can help enhance disease-related phenotypes in iPSCs.
Glucocerebrosidase 1 and leucine-rich repeat kinase 2 in Parkinson disease and interplay between the two genes
By Michelle onReview: This review focuses on the endolysosomal pathway roles of GBA and LRRK2, highlighting the role and activity of Rab GTPases as LRRK2 substrates.
powerEQTL: an R package and shiny application for sample size and power calculation of bulk tissue and single-cell eQTL analysis
By taliag onPublished: Genome-wide association studies (GWAS) reveal thousands of genetic loci. To understand the causality of the genetic variants, many researchers employ expression of quantitative trait locus (eQTL) analysis. The authors created a simplified, user-friendly R package called powerEQTL to aid in performing the power calculations needed for eQTL analysis. View original preprint.
Mapping the Diverse and Inclusive Future of Parkinson’s Disease Genetics and Its Widespread Impact
By Michelle onReview: This review discuss the need for, inclusion of, and barriers to understudied ancestral groups in PD genetics research. They also provide an overview of PD clinical genetics and describe the future of PD genetics through the lens of collaborative initiatives.
The remote assessment of parkinsonism supporting the ongoing development of interventions in Gaucher disease
By taliag onPublished: This methodology report assesses a large cohort of GBA mutation carriers with the goal of developing procedures to diagnose PD earlier. View original preprint.
GP2: The Global Parkinson’s Genetics Program
By Michelle onOp-Ed: This article summarizes The Global Parkinson’s Genetics Program (GP2) and outlines its mission, path, deliverables, and principles.
Microbes and Parkinson’s Disease: from associations to mechanisms.
By Michelle onReview: This review dissects the microbial contributions to PD with a particular focus on recent advances and rodent models that can be used for microorganism hypothesis testing.
Structural Biology of LRRK2 and its Interaction with Microtubules
By taliag onReview: This review focuses on new insights into the stucture of LRRK2's cytosolic and microtubule-bound forms and challenges going forward.
Biomarkers of neurodegeneration and glial activation validated in Alzheimer’s disease assessed in longitudinal cerebrospinal fluid samples of Parkinson’s disease
By taliag onPublished: This article assessed an established biomarker panel, validated in Alzheimer’s Disease, in a PD cohort.
The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model
By Michelle onPublished: Tau neuronal aggregation is a driver of some neurodegenerative disorders. These toxic aggregates form when affected cells release aggregate seeds which are then internalized by unaffected cells. The authors show that a protein,Clusterin, delays Tau aggregation and suppresses seeding activity. View original preprint.
Longitudinal Analysis of Multiple Neurotransmitter Metabolites in Cerebrospinal Fluid in Early Parkinson’s Disease
By taliag onPublished: This study aimed to quantifiy multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis.
The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends
By Michelle onPublished: Irreversible toxic aggregates are a hallmark of neurodegenerative diseases, such as alpha-synuclein in PD. Using microfluidic diffusional sizing, the authors show that the molecular chaperone family Hsp70 (specifically Hsc70, DnaJB, and Apg2) can completely dissolve alpha-synuclein aggregation and revert it back to its monomeric state.
Quantitative proteomics reveals the selectivity of ubiquitin-binding autophagy receptors in the turnover of damaged lysosomes by lysophagy
By Michelle onPublished: The authors used proteomics to develop a quantitative snapshot of the proteins involved in lysophagy. Among the proteins identified, they found that TAX1BP1 and TBK1 are both required for lysophagy. View original preprint.
In situ architecture of neuronal α-Synuclein inclusions
By Michelle onPublished: Alpha-synuclein aggregation has been associated with Parkinson’s disease. Using cutting-edge imaging tools, the authors show neuronal alpha-synuclein inclusions within their native states. Further, they show that these aggregates are intermixed with cellular organelles and how aggregation spreads across the brain. View original preprint.
Seed Amplification Assay to Diagnose Early Parkinson’s and Predict Dopaminergic Deficit Progression
By taliag onPublished: This article uses an optimized high-throughput αS-SAA (based on a previously described α-Syn protein misfolding cyclic amplification (PMCA) assay)2, 5, 6 that detects αSyn aggregates in CSF, to evaluate 140 blinded samples from the Parkinson's Progression Markers Initiative (PPMI).
Vesicular dysfunction and pathways to neurodegeneration
By Michelle onIn this review, the pathways that have emerged as being critical for neuronal survival in the human brain is be discussed – illustrating the diversity of proteins and cellular events with three molecular case studies drawn from different neurological diseases.
A possible role for VPS13-family proteins in bulk lipid transfer, membrane expansion, and organelle biogenesis.
By Blythe Lloyd onReview: This review focuses on the structure and function of the VPS13 family of proteins and discusses the prevailing hypthoses in the field regarding its role in lipid transport.