Large-scale biophysically detailed model of somatosensory thalamocortical circuits in NetPyNE
By taliag onPublished: 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 dynamics
By taliag onPublished: 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).
Unaltered T cell responses to common antigens in individuals with Parkinson’s disease
By taliag onPublished: 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 signatures
By taliag onPublished: 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.
Genetic and pharmacological reduction of CDK14 mitigates α-synuclein pathology in human neurons and in rodent models of Parkinson’s disease
By taliag onPreprint: Decreasing alpha-synuclein levels is a potential therapeutic approach for synucleinopathies. 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.
Towards a phenome-wide view of Parkinson’s disease
By taliag onPreprint: 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 disease
By taliag onRecent 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.
Highly efficient generation of isogenic pluripotent stem cell models using prime editing
By taliag onPublished: 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.
Structural basis for Parkinson’s Disease-linked LRRK2’s binding to microtubules
By taliag onPreprint: 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.
Membrane curvature sensing and stabilization by the autophagic LC3 lipidation machinery
By taliag onPreprint: 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.
In situ structural analysis reveals membrane shape transitions during autophagosome formation
By taliag onPreprint: 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.
The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system
By taliag onPublished: 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. View original preprint.
Spatial snapshots of amyloid precursor protein intramembrane processing via early endosome proteomics
By taliag onPublished: 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. View original preprint.
ggtranscript: an R package for the visualization and interpretation of transcript isoforms using ggplot2
By taliag onPublished: 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.
Local genetic correlations exist among neurodegenerative and neuropsychiatric diseases
By taliag onPreprint: 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 allele
By taliag onPublished: 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.
Association between the LRP1B and APOE loci and the development of Parkinson’s disease dementia
By taliag onPublished: Dementia is an important feature of late-stage PD. The authors used an unbiased, genome-wide approach to identify genetic polymorphisms that associate with faster development of dementia in PD patients. They identified four genetic regions that are associated with progression to dementia in PD, including APOE and three previously unknown regions. View original preprint (https://www.medrxiv.org/content/10.1101/2022.05.23.22275465v1).
Diabetes and neuroaxonal damage in Parkinson’s disease
By taliag onPublished: Those living with both PD and type 2 diabetes can present with more severe motor and cognitive symptoms. The authors investigated whether more severe neuroaxonal injury in PD patients was the cause. They confirmed these findings and found these patients had higher serum neurofilament light levels. View original preprint.
Combining biomarkers for prognostic modeling of Parkinson’s disease
By taliag onPublished: Disease progression in PD patients is variable, but blood biomarkers may be useful. The authors evaluated serum neurofilament light (NfL) as a potential prognostic biomarker for PD. They found that serum NfL provided an objective measure of neurodegeneration in PD patients. View original preprint.
Evaluation Of The Rims2 Locus As A Risk Locus For Parkinson’s Disease Dementia
By taliag onPreprint: Genome-wide association studies have identified several risk loci for PD, providing insights into the mechanisms of disease initiation. Previously, the RIMS2 locus was identified as a determinant of dementia in PD. The authors evaluated 2536 individuals evaluated it, but found no association between RIMS2 and development of PD-related dementia.