RBG Motif Bridge-Like Lipid Transport Proteins: Structure, Functions, and Open Questions
By onThe life of eukaryotic cells requires the transport of lipids between membranes, which are separated by the aqueous environment of the cytosol. Vesicle-mediated traffic along the secretory and endocytic pathways and lipid transfer proteins (LTPs) cooperate in this transport. Until recently, known LTPs were shown to carry one or a few lipids at a time and were thought to mediate transport by shuttle-like mechanisms. Over the last few years, a new family of LTPs has been discovered that is defined by a repeating β-groove (RBG) rod-like structure with a hydrophobic channel running along their entire length. This structure and the localization of these proteins at membrane contact sites suggest a bridge-like mechanism of lipid transport. Mutations in some of these proteins result in neurodegenerative diseases. Here we review the known properties and well-established or putative physiological roles of these proteins, and we highlight the many questions that remain open about their functions.
Membrane curvature sensing and stabilization by the autophagic LC3 lipidation machinery
By onDuring autophagy initiation, the curved phagophore is stabilized. Using in vitro reconstitution and MD simulations, authors show that WIPI2 and ATG16L1 bind these curved phagophores and the ATG12-5-16L1 complex is responsible for membrane curvature.
Evaluation of an adapted semi-automated DNA extraction for human salivary shotgun metagenomics
By onThis study demonstrates that the authors’ semi-automated protocol is suitable for shotgun metagenomic analysis.
KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy
By onThe authors provide additional support for KAT8 inhibition as a regulator of mitophagy and autophagy processes.
Biomarkers of neurodegeneration and glial activation validated in Alzheimer’s disease assessed in longitudinal cerebrospinal fluid samples of Parkinson’s disease
By onSeveral pathophysiological processes are involved in Parkinson’s disease (PD) and could inform in vivo biomarkers. We assessed an established biomarker panel, validated in Alzheimer’s Disease, in a PD cohort. Except for αSyn, the additional biomarkers did not differentiate PD and HC, and none showed longitudinal differences, but most markers predict cognitive decline in PD during follow-up.
Microbes and Parkinson’s Disease: from associations to mechanisms
By onSeveral microbes, including viruses, bacteria, and fungi, have been associated with an increased risk of PD in humans. Microbial infections can induce similar common pathways that are associated with PD, including systemic inflammatory responses, α-synuclein misfolding, and disruption of mitochondria. PD-associated gene mutations can impact host–microbe interactions, suggesting that even familial forms of PD may be influenced by microbes.
The longitudinal progression of autonomic dysfunction in Parkinson’s disease: a 7-year study
By onAutonomic dysfunction, including gastrointestinal, cardiovascular, and urinary dysfunction, is often present in early Parkinson's Disease (PD). However, the knowledge of the longitudinal progression of these symptoms, and the connection between different autonomic domains, is limited. Using data collected from PPMI, autonomic dysfunction was measured using the Scales for Outcomes in Parkinson's Disease (SCOPA-AUT). Symptom frequency and mean scores over 7 years were determined. At baseline, greater SCOPA-AUT total score was associated with lower UPSIT scores (r = −0.209, p = 0.006) and with greater total MDS-UDPRS III score (r = 0.218, p = 0.004).
ggtranscript: an R package for the visualization and interpretation of transcript isoforms using ggplot2
By onThe authors present ggtranscript, an R package that provides a fast and flexible method to visualize and compare transcripts from long-read sequences. This tool is an extension of ggplot2.
Sphingolipid changes in Parkinson L444P GBAmutation fibroblasts promote α-synuclein aggregation
By onIntraneuronal accumulation of aggregated α-synuclein is a pathological hallmark of Parkinson’s disease. Therefore, mechanisms capable of promoting α-synuclein deposition bear important pathogenetic implications. Mutations of the glucocerebrosidase 1 (GBA) gene represent a prevalent Parkinson’s disease risk factor. They are associated with loss of activity of a key enzyme involved in lipid metabolism, glucocerebrosidase, supporting a mechanistic relationship between abnormal α-synuclein–lipid interactions and the development of Parkinson pathology. In this study, the lipid membrane composition of fibroblasts isolated from control subjects, patients with idiopathic Parkinson’s disease and Parkinson's disease patients carrying the L444P GBA mutation (PD-GBA) was assayed using shotgun lipidomics. The lipid profile of PD-GBA fibroblasts differed significantly from that of control and idiopathic Parkinson’s disease cells. It was characterized by an overall increase in sphingolipid levels. It also featured a significant increase in the proportion of ceramide, sphingomyelin and hexosylceramide molecules with shorter chain length and a decrease in the percentage of longer-chain sphingolipids. The extent of this shift was correlated to the degree of reduction of fibroblast glucocerebrosidase activity. Lipid extracts from control and PD-GBA fibroblasts were added to recombinant α-synuclein solutions. The kinetics of α-synuclein aggregation were significantly accelerated after addition of PD-GBA extracts as compared to control samples. Amyloid fibrils collected at the end of these incubations contained lipids, indicating α-synuclein–lipid co-assembly. Lipids extracted from α-synuclein fibrils were also analysed by shotgun lipidomics. Data revealed that the lipid content of these fibrils was significantly enriched by shorter-chain sphingolipids. In a final set of experiments, control and PD-GBA fibroblasts were incubated in the presence of the small molecule chaperone ambroxol. This treatment restored glucocerebrosidase activity and sphingolipid levels and composition of PD-GBA cells. It also reversed the pro-aggregation effect that lipid extracts from PD-GBA fibroblasts had on α-synuclein. Taken together, the findings of this study indicate that the L444P GBA mutation and consequent enzymatic loss are associated with a distinctly altered membrane lipid profile that provides a biological fingerprint of this mutation in Parkinson fibroblasts. This altered lipid profile could also be an indicator of increased risk for α-synuclein aggregate pathology.
Feed-forward metabotropic signaling by Cav1 Ca2+ channels supports pacemaking in pedunculopontine cholinergic neurons
By onCholinergic neurons (CNs) in the pedunculopontine nucleus (PPN) are lost in the course of Parkinson’s disease. PPN CNs have a distinctive physiological phenotype that shares only some of the features of other selectively vulnerable neurons in PD.
PKC isoforms activate LRRK1 kinase by phosphorylating conserved residues (Ser1064, Ser1074 and Thr1075) within the CORB GTPase domain
By onLeucine-rich-repeat-kinase 1 (LRRK1) and its homologue LRRK2 are multidomain kinases. Here, the authors study the mechanism controlling LRRK1 activity and reveal a novel unexpected activation mechanism.
Spatial transcriptomics reveals molecular dysfunction associated with Lewy pathology
By onThe results identify neurons vulnerable to Lewy pathology in the PD cortex and identify a conserved signature of molecular dysfunction in both mice and humans.
Structural basis for membrane recruitment of ATG16L1 by WIPI2 in Autophagy
By onThe authors showed through structural determination how ATG16L1 and WIPI2 interact and compared the other WIPI proteins showing the variety of mechanisms of membrane recruitment by WIPI proteins.
Brain Repair by Cell Replacement via In Situ Neuronal Reprogramming
By onNeurodegenerative diseases, characterized by progressive neural loss, have been some of the most challenging medical problems in aging societies. Treatment strategies such as symptom management have little impact on disease progression, while intervention with specific disease mechanisms may only slow down disease progression. One therapeutic strategy that has the potential to reverse the disease phenotype is to replenish neurons and rebuild the pathway lost to degeneration. Although it is generally believed that the central nervous system has lost the capability to regenerate, increasing evidence indicates that the brain is more plastic than previously thought, containing perhaps the biggest repertoire of cells with latent neurogenic programs in the body. 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.
Association between the LRP1B and APOE loci and the development of Parkinson’s disease dementia
By onGenetic analysis of 3,964 PD cases revealed APOE-ϵ4 allele and new loci as risk factors for PD dementia progression, implicating amyloid pathway in PDD development and potential for amyloid-targeting therapy.
Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex
By onAuthors determine cryo-EM structure of human ULK1C core and its complex with PI3KC3-C1. ULK1C core undergoes a rearrangement from 2:1:1 to 2:2:2 stoichiometry, suggesting a structural mechanism for autophagy initiation.
The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends
By onUsing 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.
Phenotypic effect of GBA1 variants in individuals with and without Parkinson disease: the RAPSODI study
By onThe authors’ results support previous evidence that GBA1-positive PD has a specific phenotype with more severe non-motor symptoms. The authors did not reproduce previous findings of more frequent prodromal PD signs in non-affected GBA1 carriers.
A feed-forward pathway drives LRRK2 kinase membrane recruitment and activation
By onLRRK2 interacts with Rab8A and Rab10 at specific binding sites, enhancing LRRK2 kinase activity on membranes. This feed-forward pathway regulates LRRK2 activation and substrate phosphorylation.
Multiscale model of primary motor cortex circuits predicts in vivo cell type-specific, behavioral state-dependent dynamics
By onA detailed multiscale model of mouse primary motor cortex accurately predicted responses to behavioral states and manipulations, aiding in understanding cortical function at different scales.
