Glucocerebrosidase, a Parkinson´s disease-associated protein, is imported into mitochondria and regulates complex I assembly and functionon
Mutations in the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson’s disease (PD). Here, the authors employed global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration.
Protein network analysis links the NSL complex to Parkinson’s disease and mitochondrial biologyon
A bioinformatics approach was taken to investigate the proteome of the NSL complex, to unpick its relevance to PD progression. The authors’ data points to NSL complex members OGT and WDR5 as key drivers of this increased PD association. These findings strengthen a role for mitochondrial quality control in both familial and sporadic disease.
A combined cell and gene therapy approach for homotopic reconstruction of midbrain dopamine pathways using human pluripotent stem cellson
These results demonstrate the remarkable capacity for achieving functional and anatomically precise reconstruction of long-distance circuitry in the adult brain by matching appropriate growth-factor signaling to grafting of specific cell types.
ASAP Blueprint for Collaborative Open Scienceon
This Blueprint presents initial findings on how ASAP’s approach to open science has solidified and evolved over its first three years, data and metrics on progress, and CC-BY versions of assets that can be adopted and adapted by others. ASAP plans to update the Blueprint with new findings and assets on a regular basis.
Basal ganglia neurons in healthy and Parkinsonian primates generate recurring sequences of spikeson
The authors conclude that basal ganglia neurons fire in recognizable sequences of ISIs, whose incidence is influenced by the induction of parkinsonism.
Brain repair by cell replacement via in situ neuronal reprogrammingon
This review focuses on key advances in generating new neurons through in situ neuronal reprogramming, which is tied to fundamental questions regarding adult neurogenesis, cell source, and mechanisms for neuronal reprogramming, as well as the ability of new neurons to integrate into the existing circuitry.
Genome-wide determinants of mortality and clinical progression in Parkinson’s diseaseon
Here the authors examined the impact of gene variants on mortality and cognitive impairment in PD.
HyDrop: droplet-based scATAC-seq and scRNA-seq using dissolvable hydrogel beadson
The data available in this repository can be used to replicate all the figures in the authors’ manuscript using their data analysis tutorial available here: https://github.com/aertslab/hydrop_data_analysis
PKC isoforms activate LRRK1 kinase by phosphorylating conserved residues (Ser1064, Ser1074, and Thr1075) within the CORB GTPase domainon
Leucine-rich-repeat-kinase 1 (LRRK1) and its homologue LRRK2 are multidomain kinases possessing a ROC-CORA-CORB containing GTPase domain and phosphorylate distinct Rab proteins. LRRK1 loss of function mutations cause the bone disorder osteosclerotic metaphyseal dysplasia, whereas LRRK2 missense mutations that enhance kinase activity cause PD. Here, the authors study the mechanism controlling LRRK1 activity and reveal a novel unexpected activation mechanism. View preprint.
The chromatin modulating NSL complex regulates genes and pathways genetically linked to Parkinson’s diseaseon
Two Parkinson's disease candidate genes, KAT8 and KANSL1, identified through genome-wide studies and a PINK1-mitophagy screen, encode part of the histone acetylating non-specific lethal complex. Here, the authors sought to identify whether the non-specific lethal complex has potential regulatory relationships with other genes associated with Parkinson's disease in human brain.
Targeted neuronal activation of the gastrointestinal tract shapes the environment of the gut in miceon
The enteric nervous system (ENS) integrates cues from the brain and from local signals in the gut to coordinate responses that shape the intestinal milieu. Here, the authors examine the role of neurons in modulating intestinal physiology, mucosal immunity, and gut microbiome structure.
CRISPR/Cas9-based functional genomics in human induced pluripotent stem cell–derived models: Can “the stars align” for neurodegenerative diseases?on
Viewpoint article on CRISPR/Cas9-based functional genomics in human induced pluripotent stem cell–derived models.
Orchestration of selective autophagy by cargo receptorson
Review: Selective autophagy represents a major pathway for the degradation of cargo material. The authors review recent insights into the mechanisms of action of cargo receptors in selective autophagy by focusing on the roles of sequestosome-like cargo receptors in the degradation of misfolded, ubiquitinated proteins and damaged mitochondria.
Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusionson
Preprint: Intracellular inclusions accompanying neurodegeneration are histopathologically and ultrastructurally heterogeneous but the significance of this heterogeneity is unclear. iPSC models do not form inclusions in a reasonable timeframe and suffer from limited tractability. The authors developed an iPSC toolbox utilizing piggyBac-based or targeted transgenes to rapidly induce CNS cells with concomitant expression of aggregation-prone proteins.
Serine-129 phosphorylation of α-synuclein is a trigger for physiologic protein-protein interactions and synaptic functionon
Preprint: Phosphorylation of α-synuclein at the Serine-129 site (α-syn Ser129P) is an established pathologic hallmark of synucleinopathies, and also a therapeutic target. The authors noticed that unlike native (total) α-syn that is widely expressed throughout the brain, the overall pattern of α-syn Ser129P is restricted, suggesting intrinsic regulation and putative physiologic roles.
Novel green fluorescent polyamines to analyze ATP13A2 and ATP13A3 activity in the mammalian polyamine transport systemon
Preprint: Cells acquire the polyamines putrescine (PUT), spermidine (SPD), and spermine (SPM) via the complementary action of polyamine uptake and synthesis pathways. The endosomal P5B-type ATPases ATP13A2 and ATP13A3 emerge as major determinants of mammalian polyamine uptake. Our biochemical evidence shows that fluorescently labeled polyamines are genuine substrates of ATP13A2.
Golgi-IP, a novel tool for multimodal analysis of Golgi molecular contenton
Preprint: To allow the study of the Golgi at high resolution, we report a rapid immunoprecipitation technique (Golgi-IP) to isolate intact Golgi mini-stacks for subsequent analysis of their content. We then established an analysis pipeline using liquid chromatography coupled with mass spectrometry to characterize the human Golgi proteome, metabolome and lipidome.
Quantitative mapping of autophagic cargo during nutrient stress reveals YIPF3-YIPF4 as membrane receptors for Golgiphagyon
Preprint: The authors use orthogonal proteomic strategies to provide a global molecular inventory of autophagic cargo during nutrient stress in mammalian cell lines. Through prioritization of autophagic cargo, we identify a heterodimeric pair of membrane-embedded proteins, YIPF3 and YIPF4, as receptors for Golgiphagy.
Sex-specific microglial responses to glucocerebrosidase inhibition: relevance to GBA1-linked Parkinson’s diseaseon
Preprint: To elucidate the impact of sex-specific microglia heterogenicity to the susceptibility of neuronal stress, the authors analyzed the dynamic changes in shape and motility occurring in primary mouse microglia following pro-inflammatory or neurotoxic insults, thus finding sex-specific responses of microglial subpopulations.
More of less: novel multi-ome profiling of single human neuronson
Review: Epigenetic modifications to DNA and chromatin interact to influence gene expression and cellular phenotypes, but defining these omics layers in complex tissues is a daunting task. In this issue of Cell Genomics, Luo et al. describe a novel single-cell multi-omic method, simultaneously profiling transcriptome, DNA methylome, and chromatin accessibility, to shed light on human neurons.