Tonic dendritic GABA release by substantia nigra dopaminergic neurons
By onTo characterize the actions of dopamine on substantia nigra pars reticulata (SNr) GABAergic neurons, optogenetic and electrophysiological tools were used in ex vivo mouse brain slices to monitor synaptic transmission arising from neurons.
Activity-Dependent Remodeling of Corticostriatal Axonal Boutons During Motor Learning
By onThe authors assess the activity and structural plasticity of corticostriatal axons during learning in the adult mouse brain.
Refinement of efficient encodings of movement in the dorsolateral striatum throughout learning
By onThe striatum is required for normal action selection, movement, and sensorimotor learning. Although action-specific striatal ensembles have been well documented, it is not well understood how these ensembles are formed and how their dynamics may evolve throughout motor learning. Here we used longitudinal 2-photon Ca2+ imaging of dorsal striatal neurons in head-fixed mice as they learned to self-generate locomotion. We observed a significant activation of both direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs, respectively) during early locomotion bouts and sessions that gradually decreased over time. For dSPNs, onset- and offset-ensembles were gradually refined from active motion-nonspecific cells. iSPN ensembles emerged from neurons initially active during opponent actions before becoming onset- or offset-specific. Our results show that as striatal ensembles are progressively refined, the number of active nonspecific striatal neurons decrease and the overall efficiency of the striatum information encoding for learned actions increases.
Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases
By onMouse α-synuclein fibrils have been studied to understand Parkinson's disease and multiple system atrophy. They differ from human fibrils in structure and behavior, impacting research on related diseases and potential treatments.
Isolation and Lipidomic Profiling of Neuronal Lipid Droplets: Unveiling the Lipid Landscape for insights into Neurodegenerative Disorders
By onRecent advances have expanded the role of lipid droplets (LDs) beyond passive lipid storage, implicating their involvement in various metabolic processes across mammalian tissues. Neuronal LDs, long debated in existence, have been identified in several neural structures, raising questions about their contribution to neurodegenerative disorders. Elucidating the specific chemical makeup of these organelles within neurons is critical for understanding their implication in neural pathologies. This study outlines an improved methodology to stimulate and isolate mature LDs from cultured primary neurons, offering insights into their unique lipid-protein composition. Integrating this method with high-throughput techniques may unveil disease-specific alterations in lipid metabolism, providing avenues for potential therapeutic interventions.
Lysosome damage triggers acute formation of ER to lysosomes membrane tethers mediated by the bridge-like lipid transport protein VPS13C
By onBased on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson’s disease (PD). Here we show that VPS13C, a bridge-like lipid transport protein and a PD gene, is a sensor of lysosome stress/damage. Upon lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires release of a brake, most likely an intramolecular interaction within VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. While another PD protein, LRRK2, is also recruited to stressed/damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the putative role of VPS13 proteins in bulk lipid transport, these findings suggest lipid delivery to lysosomes by VPS13C is part of an early response to lysosome damage.
The diversity of SNCA transcripts in neurons, and its impact on antisense oligonucleotide therapeutics
By onLong-read RNA sequencing of SNCA in human dopaminergic neuron reveals most expression comes from alternative transcripts. Targeting these with ASOs effective reversal of PD pathology, offering insights for RNA therapies + protein isoform differences.
Network nature of ligand-receptor interactions underlies disease comorbidity in the brain
By onNeurodegenerative disorders have overlapping symptoms and high comorbidity rates. The authors investigated whether ligand-receptor interactions (LRIs) are a mechanism by which distinct genes can impact overlapping outcomes.
Transcriptional pathobiology and multi-omics predictors for Parkinson’s disease
By onStudy identifies PD-related RNAs in blood, incl. genes, circRNAs, eRNAs. Genes linked to neutrophil activation, TNF-alpha signaling. ML model predicts PD diagnosis with AUC 0.89. Offers potential for early diagnosis and biomarker development in PD.
Dissociation of novel open loop from ventral putamen to motor areas from classic closed loop in humans II: task-based function
By onHumans increase the speed of their movements when motivated by incentives. The authors analyzed the profile of two circuits involving putamen and motor cortical areas to assess the interplay between incentivization and motor output.
Mitochondrial oxidant stress promotes α-synuclein aggregation and spreading in mice with mutated glucocerebrosidase
By onIn this study, heterozygous expression of a common glucocerebrosidase variant, was found to exacerbate α-synuclein aggregation and spreading in a mouse model of Parkinson-like pathology targeting neurons of the medullary vagal system.
A comparative analysis of Parkinson’s disease and inflammatory bowel disease gut microbiomes highlights shared depletions in key butyrate-producing bacteria
By onEpidemiological studies show a link between IBD and PD. Gut microbiome alterations, specifically depletions in SCFA-producing bacteria, may contribute to this connection. Comparing PD and IBD microbiomes can help identify shared features.
Locus coeruleus injury modulates ventral midbrain neuroinflammation during DSS-induced colitis
By onPD is preceded by non-motor symptoms like gastrointestinal issues and mood changes. A two-hit mouse model shows gut inflammation and LC lesioning affect neuroimmune responses, highlighting the role of NEergic interventions in PD progression.
Gut-Initiated Alpha Synuclein Fibrils Drive Parkinson’s Disease Phenotypes: Temporal Mapping of non-Motor Symptoms and REM Sleep Behavior Disorder
By onPropagation of αSyn from the gut-to-the-brain induces RBD and several non-motor and motor phenotypes of Parkinson’s disease.
Development of a Simplified Smell Test to Identify Patients with Typical Parkinson’s as Informed by Multiple Cohorts, Machine Learning and External Validation
By onReduced olfaction is a common feature of typical Parkinson disease (PD) and dementia with Lewy bodies (DLB). We have created a simplified smell test based on seven specific odorants that can distinguish PD/DLB patients from healthy controls.
Experimental and Computational Methods for Allelic Imbalance Analysis from Single-Nucleus RNA-seq Data
By onWe systematically investigated experimental and computational design choices for their effects on allelic imbalance analysis in droplet-based snRNA-seq data from human samples. We show that many factors, including read length, sequencing technology,
GEARBOCS: An Adeno Associated Virus Tool for In Vivo Gene Editing in Astrocytes
By onGEARBOCS is a non-invasive method for precise gene editing in astrocytes using CRISPR/Cas9. It allows knockout, tagging, and reporter knock-in strategies, revealing the roles of Sparcl1 and Vamp2 in synapse maintenance in the mouse visual cortex.
Functional efficacy of the MAO-B inhibitor safinamide in murine substantia nigra pars compacta dopaminergic neurons in vitro: a comparative study with tranylcypromine
By onSafinamide (SAF) is used for PD by enhancing dopamine signal. SAF prolongs recovery from dopamine-mediated firing inhibition in SNpc DAergic neurons, mildly compared to tranylcypromine, suggesting multiple sites of action for SAF's therapeutics.
The Role of Alpha-Synuclein Pathology
By onAlpha-Synuclein (aSyn) is key protein in PD and other synucleinopathies, causing neurodegeneration. Despite its importance, there is a lack of consensus on markers to define aSyn aggregates, highlighting the need for better research tools and models.
Peripheral Blood Immune Cells from Individuals with Parkinson’s Disease or Inflammatory Bowel Disease Share Deficits in Iron Storage and Transport that are Modulated by Non-Steroidal Anti-Inflammatory Drugs
By onParkinson's (PD) involves dysregulated neuroimmune crosstalk and gut-brain axis inflammation. Gastrointestinal dysfunction is a common early symptom. Iron dysregulation and immune cell dysfunction may play a role, with shared features in PD an IBD.
