Synaptic Location Is a Determinant of the Detrimental Effects of α-Synuclein Pathology to Glutamatergic Transmission in the Basolateral Amygdala
By onStudy explores α-synuclein's impact on amygdala in Parkinson's. Aggregation affects cortico-BLA transmission, linked to psychiatric deficits in PD.
CURTAIN—A unique web-based tool for exploration and sharing of MS-based proteomics data
By onLinks can also be reported in publications allowing readers to further survey the reported data. The authors discuss benefits for the research community of publishing proteomic data containing a shareable web-link.
Updated Percentiles for the University of Pennsylvania Smell Identification Test in Adults 50 Years of Age and Older
By onThe University of Pennsylvania Smell Identification Test (UPSIT) is commonly used to assess olfaction and screen for early detection of disorders including Parkinson (PD) and Alzheimer disease. Our objective was to develop updated percentiles, based on substantially larger samples than previous norms, to more finely discriminate age- and sex-specific UPSIT performance among ≥50-year-old adults who may be candidates for studies of prodromal neurodegenerative diseases.
Impaired dopamine release in Parkinson’s disease
By onEvidence indicates that impaired dopamine release can result from disruption to a diverse range of Parkinson’s disease-associated genetic and molecular disturbances and can be considered a potential pathophysiological hallmark of Parkinson’s disease.
A mono- and intralink filter (mi-filter) to reduce false identifications in cross-linking mass spectrometry data
By onCross-linking mass spectrometry (XL-MS) has become an indispensable tool for the emerging field of systems structural biology over the recent years. However, the confidence in individual protein–protein interactions (PPIs) depends on the correct assessment of individual inter-protein cross-links. In this article, we describe a mono- and intralink filter (mi-filter) that is applicable to any kind of cross-linking data and workflow. It stipulates that only proteins for which at least one monolink or intra-protein cross-link has been identified within a given data set are considered for an inter-protein cross-link and therefore participate in a PPI. We show that this simple and intuitive filter has a dramatic effect on different types of cross-linking data ranging from individual protein complexes over medium-complexity affinity enrichments to proteome-wide cell lysates and significantly reduces the number of false-positive identifications for inter-protein links in all these types of XL-MS data.
Unconventional secretion of α-synuclein mediated by palmitoylated DNAJC5 oligomers
By onThe secretion of endogenous α-syn mediated by DNAJC5 is found in a human neuroblastoma cell line, The authors propose that DNAJC5 forms a palmitoylated oligomer to accommodate and export α-syn.
Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice
By onIn Parkinson’s disease (PD), motor dysfunctions only become apparent after extensive loss of DA innervation. This resilience has been hypothesized to be due to the ability of many motor behaviors to be sustained through a diffuse basal tone of DA; but experimental evidence for this is limited. Here we show that conditional deletion of the calcium sensor synaptotagmin-1 (Syt1) in DA neurons (Syt1 cKODA mice) abrogates most activity-dependent axonal DA release in the striatum and mesencephalon, leaving somatodendritic (STD) DA release intact. Strikingly, Syt1 cKODA mice showed intact performance in multiple unconditioned DA-dependent motor tasks and even in a task evaluating conditioned motivation for food. Considering that basal extracellular DA levels in the striatum were unchanged, our findings suggest that activity-dependent DA release is dispensable for such tasks and that they can be sustained by a basal tone of extracellular DA. Taken together, our findings reveal the striking resilience of DA-dependent motor functions in the context of a near-abolition of phasic DA release, shedding new light on why extensive loss of DA innervation is required to reveal motor dysfunctions in PD.
Interaction of an α-synuclein epitope with HLA-DRB1*15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease
By onInteraction of α-syn32-46 and HLA-DRB1*15:0 is critical for gut inflammation and CD4+ T cell-mediated loss of enteric neurons in humanized mice, suggesting potential mechanisms of prodromal enteric PD.
The chaperone Clusterin in neurodegeneration−friend or foe?
By onThe authors review the diverse functions of Clusterin in the pathogenesis of neurodegenerative diseases, focusing on evidence that Clusterin may act either as a suppressor or enhancer of pathology.
LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition
By onCells maintain optimal levels of lysosome degradative activity to protect against pathogens, clear waste, and generate nutrients. Here, we show that LRRK2, a protein that is tightly linked to Parkinson’s disease, negatively regulates lysosome degradative activity in macrophages and microglia via a transcriptional mechanism. Depletion of LRRK2 and inhibition of LRRK2 kinase activity enhanced lysosomal proteolytic activity and increased the expression of multiple lysosomal hydrolases. Conversely, the kinase hyperactive LRRK2 G2019S Parkinson’s disease mutant suppressed lysosomal degradative activity and gene expression. We identified MiT-TFE transcription factors (TFE3, TFEB, and MITF) as mediators of LRRK2-dependent control of lysosomal gene expression. LRRK2 negatively regulated the abundance and nuclear localization of these transcription factors and their depletion prevented LRRK2-dependent changes in lysosome protein levels. These observations define a role for LRRK2 in controlling lysosome degradative activity and support a model wherein LRRK2 hyperactivity may increase Parkinson’s disease risk by suppressing lysosome degradative activity.
GBA Variants and Parkinson Disease: Mechanisms and Treatments
By onThis review discusses the pathways associated with GBA-PD and highlights potential treatments which may act to target the lysosomal enzyme glucocerebrosidase and prevent neurodegeneration.
Reduced Thalamic Excitation to Motor Cortical Pyramidal Tract Neurons in Parkinsonism
By onThe current data suggests that cell subtype- and synapse-specific adaptations in M1 contribute to altered cortical outputs in parkinsonism and are important aspects of PD pat
Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism
By onMutations in GBA1, the gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher’s disease, are the most frequent genetic risk factor for Parkinson’s disease (PD). Here, we employ 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. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration.
Structural basis for the specificity of PPM1H phosphatase for Rab GTPases
By onLRRK2 acts by adding a phosphate group to enzymes known as Rab GTPases, which causes new biological events. The authors analyzed the structure of an enzyme, PPM1H, that counteracts LRRK2 by removing the phosphate group it adds to Rab GTPases.
ASAP Blueprint for Collaborative Open Science
By onThis 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.
Detection of mosaic and population-level structural variants with Sniffles2
By onSniffles2 is a fast and accurate tool for identifying complex genomic alterations using long -read data.
Conserved and cell type-specific transcriptional responses to IFN-γ in the ventral midbrain
By onNeurons present antigens when exposed to IFN-γ, leading to MHC-I expression. IFN-γ induces MHC-I in neurons, glia, and microglia, with glia showing a stronger response. Neuronal response to IFN-γ is dependent on IFNGR signaling.
Generation of human-induced pluripotent-stem-cell-derived cortical neurons for high-throughput imaging of neurite morphology and neuron maturation
By onA STAR protocol that describes how to differentiate cryopreserved human cortical neuronal progenitors into mature cortical neurons for high-throughput imaging analysis
From Policy to Practice: Tracking an Open Science Funding Initiative
By onBy normalizing the open science and compliance process across funding bodies, ASAP hopes to simplify and streamline researcher, institutional, and funder workflows, allowing researchers to focus on science.
Therapeutic Potential of PTB Inhibition Through Converting Glial Cells to Neurons in the Brain
By onCell replacement therapy represents a promising approach for treating neurodegenerative diseases. Contrary to the common addition strategy to generate new neurons from glia by overexpressing a lineage-specific transcription factor(s), a recent study introduced a subtraction strategy by depleting a single RNA-binding protein, Ptbp1, to convert astroglia to neurons not only in vitro but also in the brain. Given its simplicity, multiple groups have attempted to validate and extend this attractive approach but have met with difficulty in lineage tracing newly induced neurons from mature astrocytes, raising the possibility of neuronal leakage as an alternative explanation for apparent astrocyte-to-neuron conversion. This review focuses on the debate over this critical issue. Importantly, multiple lines of evidence suggest that Ptbp1 depletion can convert a selective subpopulation of glial cells into neurons and, via this and other mechanisms, reverse deficits in a Parkinson's disease model, emphasizing the importance of future efforts in exploring this therapeutic strategy.
