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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
Adeno-associated viral vectors for functional intravenous gene transfer throughout the non-human primate brain
By onCrossing the blood–brain barrier in primates is a major obstacle for gene delivery to the brain. Adeno-associated viruses (AAVs) promise robust, non-invasive gene delivery from the bloodstream to the brain. However, unlike in rodents, few neurotropic AAVs efficiently cross the blood–brain barrier in non-human primates. Here we report on AAV.CAP-Mac, an engineered variant identified by screening in adult marmosets and newborn macaques, which has improved delivery efficiency in the brains of multiple non-human primate species: marmoset, rhesus macaque and green monkey. CAP-Mac is neuron biased in infant Old World primates, exhibits broad tropism in adult rhesus macaques and is vasculature biased in adult marmosets. We demonstrate applications of a single, intravenous dose of CAP-Mac to deliver functional GCaMP for ex vivo calcium imaging across multiple brain areas, or a cocktail of fluorescent reporters for Brainbow-like labelling throughout the macaque brain, circumventing the need for germline manipulations in Old World primates. As such, CAP-Mac is shown to have potential for non-invasive systemic gene transfer in the brains of non-human primates.
Structural and biochemical insights into lipid transport by VPS13 proteins
By onVPS13 proteins are proposed to function at contact sites between organelles as bridges for lipids to move directionally and in bulk between organellar membranes. VPS13s are anchored between membranes via interactions with receptors, including both peripheral and integral membrane proteins. Here we present the crystal structure of VPS13s adaptor binding domain (VAB) complexed with a Pro-X-Pro peptide recognition motif present in one such receptor, the integral membrane protein Mcp1p, and show biochemically that other Pro-X-Pro motifs bind the VAB in the same site. We further demonstrate that Mcp1p and another integral membrane protein that interacts directly with human VPS13A, XK, are scramblases. This finding supports an emerging paradigm of a partnership between bulk lipid transport proteins and scramblases. Scramblases can re-equilibrate lipids between membrane leaflets as lipids are removed from or inserted into the cytosolic leaflet of donor and acceptor organelles, respectively, in the course of protein-mediated transport.
Simulations predict differing phase responses to excitation vs. inhibition intheta-resonant pyramidal neurons
By onThis research highlights how cortical neurons respond differently to oscillatory inputs, impacting neuronal responses to network state shifts.
Synapsin E-domain is essential for α-synuclein function
By onSynucleins and synapsins are thought to cooperate to regulate synaptic vesicle recycling, but the mechanism is not known. Here we identify the synapsin E-domain as an essential binding partner of α-syn, enabling the function of α-syn at the synapse.
Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates
By onA new NHP PD model was developed by inducing neuromelanin (NM) accumulation in dopaminergic neurons, leading to synucleinopathy and neuron degeneration similar to human PD neuropathology. Lowering NM levels may offer PD therapeutic strategies.
