A Markov random field model-based approach for differentially expressed gene detection from single-cell RNA-seq data
By onSingle-cell RNA-sequencing technology enables the identification of cell-type-specific differential gene expressions. MARBLES, a new statistical model, effectively detects DE genes across conditions.
A possible role for VPS13-family proteins in bulk lipid transfer, membrane expansion and organelle biogenesis
By onAt organelle–organelle contact sites, proteins have long been known to facilitate the rapid movement of lipids. Classically, this lipid transport involves the extraction of single lipids into a hydrophobic pocket on a lipid transport protein. Recently, a new class of lipid transporter has been described with physical characteristics that suggest these proteins are likely to function differently. They possess long hydrophobic tracts that can bind many lipids at once and physically span the entire gulf between membranes at contact sites, suggesting that they may act as bridges to facilitate bulk lipid flow. Here, we review what has been learned regarding the structure and function of this class of lipid transporters, whose best characterized members are VPS13 and ATG2 proteins, and their apparent coordination with other lipid-mobilizing proteins on organelle membranes. We also discuss the prevailing hypothesis in the field, that this type of lipid transport may facilitate membrane expansion through the bulk delivery of lipids, as well as other emerging hypotheses and questions surrounding these novel lipid transport proteins.
Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem?
By onWith over 15 FDA approved drugs on the market and numerous ongoing clinical trials, RNA therapeutics, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), have shown great potential to treat human disease. Their mechanism of action is based entirely on the sequence of validated disease-causing genes without the prerequisite knowledge of protein structure, activity or cellular location. In contrast to small molecule therapeutics that passively diffuse across the cell membrane's lipid bilayer, RNA therapeutics are too large, too charged, and/or too hydrophilic to passively diffuse across the cellular membrane and instead are taken up into cells by endocytosis. However, endosomes are also composed of a lipid bilayer barrier that results in endosomal capture and retention of 99% of RNA therapeutics with 1% or less entering the cytoplasm. Although this very low level of endosomal escape has proven sufficient for liver and some CNS disorders, it is insufficient for the vast majority of extra-hepatic diseases. Unfortunately, there are currently no acceptable solutions to the endosomal escape problem. Consequently, before RNA therapeutics can be used to treat widespread human disease, the rate-limiting delivery problem of endosomal escape must be solved in a nontoxic manner.
Peripheral neuronal activation shapes the microbiome and alters gut physiology
By onThe authors specifically activate ChAT- or TH-expressing gut-associated neurons in mice and perform multi-omics, finding that subsets of peripherally-activated neurons differentially regulate the gut microbiome and host GI physiology.
A step forward for LRRK2 inhibitors in Parkinson’s disease
By onIn common with the majority of neurodegenerative diseases, there is an urgent and pressing need for novel disease modifying therapies for Parkinson’s disease (PD). Reporting the results of the first human trial for kinase inhibitors of Leucine Rich Repeat Kinase 2 (LRRK2), Jennings and co-workers presented an important advance along the drug development pathway for a target that has long been a priority for the Parkinson’s research community. The focus discusses several topics including: functional characterisation of LRRK2 and the impact of mutations and a key role for altered kinase function in disease; the human genetics of the LRRK2 locus; the outcome of a first-in-human clinical trial for LRRK2 kinase inhibitors by Denali therapeutics, LRRK2 kinase inhibition as a therapeutic strategy in humans; the strategy of using antisense oligonucleotide knockdown approach and the challenges faced by clinical trials – measuring outcomes in chronic, slowly progressing disorders with variable rates of progression.
Mutations in Parkinsonism-linked endocytic proteins synaptojanin1 and auxilin have synergistic effects on dopaminergic axonal pathology
By onParkinson's disease (PD) is a neurodegenerative disorder characterized by defective dopaminergic (DAergic) input to the striatum. Mutations in two genes encoding synaptically enriched clathrin-uncoating factors, synaptojanin 1 (SJ1) and auxilin, have been implicated in atypical Parkinsonism. SJ1 knock-in (SJ1-KIRQ) mice carrying a disease-linked mutation display neurological manifestations reminiscent of Parkinsonism. Here we report that auxilin knockout (Aux-KO) mice display dystrophic changes of a subset of nigrostriatal DAergic terminals similar to those of SJ1-KIRQ mice. Furthermore, Aux-KO/SJ1-KIRQ double mutant mice have shorter lifespan and more severe synaptic defects than single mutant mice. These include increase in dystrophic striatal nerve terminals positive for DAergic markers and for the PD risk protein SV2C, as well as adaptive changes in striatal interneurons. The synergistic effect of the two mutations demonstrates a special lability of DAergic neurons to defects in clathrin uncoating, with implications for PD pathogenesis in at least some forms of this condition.
Mitoguardin-2–mediated lipid transfer preserves mitochondrial morphology and lipid droplet formation
By onLipid transport proteins at membrane contacts, where organelles are closely apposed, are critical in redistributing lipids from the endoplasmic reticulum (ER), where they are made, to other cellular membranes. Such protein-mediated transfer is especially important for maintaining organelles disconnected from secretory pathways, like mitochondria. We identify mitoguardin-2, a mitochondrial protein at contacts with the ER and/or lipid droplets (LDs), as a lipid transporter. An x-ray structure shows that the C-terminal domain of mitoguardin-2 has a hydrophobic cavity that binds lipids. Mass spectrometry analysis reveals that both glycerophospholipids and free-fatty acids co-purify with mitoguardin-2 from cells, and that each mitoguardin-2 can accommodate up to two lipids. Mitoguardin-2 transfers glycerophospholipids between membranes in vitro, and this transport ability is required for roles both in mitochondrial and LD biology. While it is not established that protein-mediated transfer at contacts plays a role in LD metabolism, our findings raise the possibility that mitoguardin-2 functions in transporting fatty acids and glycerophospholipids at mitochondria-LD contacts.
Parkinson’s disease and cancer: a systematic review and meta-analysis of over 17 million participants
By onThe authors examined risk association between Parkinson’s disease and cancer using data from 63 publications. With the exception of melanoma, the authors found that the risk association of Parkinson’s disease and cancer was inversely related.
Coordinating a new approach to basic research into Parkinson’s disease
By onThis article introduces the Aligning Science Across Parkinson's (ASAP) initiative by taking a deep dive into the planning of the initiative, scientific themes, objectives, and outlook.
Erythroid Differentiation Dependent Interaction of VPS13A with XK at the Plasma Membrane of K562 Cells
By onMutations in VPS13A and XK lead to Chorea Acanthocytosis and McLeod syndrome, causing neurodegeneration and abnormal red blood cells. VPS13A binds XK at the ER and plasma membrane contacts in differentiated erythroblasts.
Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease
By onAuxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson's disease (PD). Here, we utilized auxilin knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. Auxilin KO mice display cardinal features of PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Significantly, treatment with L-DOPA ameliorated motor deficits. Unbiased proteomic and neurochemical analyses of auxilin KO brains indicated dopamine dyshomeostasis. We validated these findings by demonstrating slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. Defective SV protein sorting and elevated synaptic autophagy also contribute to ineffective dopamine sequestration and compartmentalization, ultimately leading to neurodegeneration. This study provides insights into how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD.
Orchestration of selective autophagy by cargo receptors
By onThe 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.
Genome-wide screen reveals Rab12 GTPase as a critical activator of Parkinson’s disease-linked LRRK2 kinase
By onThe data support a model in which Rab12 binding to a new site in the LRRK2 Armadillo domain activates LRRK2 kinase for Rab phosphorylation
Impact of 100 LRRK2 variants linked to Parkinson’s Disease on kinase activity and microtubule binding
By onThis study systematically investigates 100 LRRK2 variants linked to PD, and provides rationale for variant carrier inclusion/exclusion in ongoing and future LRRK2 inhibitor clinical trials.
Loss of tau expression attenuates neurodegeneration associated with α-synucleinopathy
By onThe authors examine the role of tau in the onset and progression of αS pathology using a transgenic mouse model of α-synucleinopathy lacking mouse tau expression.
Genome-wide Analysis of Motor Progression in Parkinson Disease
By onThe genetic basis of Parkinson disease (PD) motor progression is largely unknown. Previous studies of the genetics of PD progression have included small cohorts and shown a limited overlap with genetic PD risk factors from case-control studies. Here, we have studied genomic variation associated with PD motor severity and early-stage progression in large longitudinal cohorts to help to define the biology of PD progression and potential new drug targets.
Local genetic correlations exist among neurodegenerative and neuropsychiatric diseases
By onGenetic correlation between neurodegenerative and neuropsychiatric diseases was explored using local rg analysis. Unique relationships were found, suggesting shared genetic mechanisms and potential therapeutic targets in complex diseases.
Who is at Risk of Parkinson Disease? Refining the Preclinical Phase of GBA1 and LRRK2 Variant Carriers: a Clinical, Biochemical, and Imaging Approach
By onPurpose of Review Genetic variants in GBA1 and LRRK2 genes are the commonest genetic risk factor for Parkinson disease (PD); however, the preclinical profile of GBA1 and LRRK2 variant carriers who will develop PD is unclear. This review aims to highlight the more sensitive markers that can stratify PD risk in non-manifesting GBA1 and LRRK2 variant carriers. Recent Findings Several case–control and a few longitudinal studies evaluated clinical, biochemical, and neuroimaging markers within cohorts of non-manifesting carriers of GBA1 and LRRK2 variants. Summary Despite similar levels of penetrance of PD in GBA1 and LRRK2 variant carriers (10–30%), these individuals have distinct preclinical profiles. GBA1 variant carriers at higher risk of PD can present with prodromal symptoms suggestive of PD (hyposmia), display increased α-synuclein levels in peripheral blood mononuclear cells, and show dopamine transporter abnormalities. LRRK2 variant carriers at higher risk of PD might show subtle motor abnormalities, but no prodromal symptoms, higher exposure to some environmental factors (non-steroid anti-inflammatory drugs), and peripheral inflammatory profile. This information will help clinicians tailor appropriate screening tests and counseling and facilitate researchers in the development of predictive markers, disease-modifying treatments, and selection of healthy individuals who might benefit from preventive interventions.
Hydrop enables droplet-based single-cell ATAC-seq and single-cell RNA-seq using dissolvable hydrogel beads
By onThe data available in this repository can be used to replicate all the figures in the authors’ manuscript using their data analysis tutorial available at https://github.com/aertslab/hydrop_data_analysis.
Proteostasis and lysosomal quality control deficits in Alzheimer’s disease neurons
By onLysosomal quality control (LQC) pathways are notably impaired in both aging and AD, leading to neuronal vulnerability and cytotoxicity. Neurons show amyloid-β inclusions, and enhancing lysosomal function can help alleviate AD-related pathologies.
