Article Archive

Pathological forms of α-synuclein contribute to Parkinson’s disease (PD). Most cases of PD are believed to arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms and pathology in animals. Here, the authors explore how the microbiome may impact PD-associated genetic risks.

Quantifying the number of synapses from light microscopy images enables screening the impacts of experimental manipulations on synapse development. This approach utilizes low-throughput analysis methods that are challenging to learn and results are variable between experimenters. The authors developed SynBot, which automates imaging analysis.

Preprint: The authors assess the activity and structural plasticity of corticostriatal axons during learning in the adult mouse brain.

Preprint: The striatum is required for normal action selection, movement, and sensorimotor learning. Here, the authors assess how striatal ensembles are formed and how their dynamics may evolve throughout motor learning.

Preprint: Mutations in genes that regulate mitophagy, a key mitochondrial quality control pathway, are causative for neurological disorders including Parkinson’s. Here, the authors identify a novel stress response pathway activated by mitochondrial damage that regulates mitophagy in neurons.

Published: The authors designed a new micro-fiber array approach capable of chronically measuring and optogenetically manipulating local dynamics across over 100 targeted locations simultaneously in head-fixed and freely moving mice, enabling the investigation of cell-type and neurotransmitter-specific signals over arbitrary 3D volumes at a spatial resolution and coverage previously inaccessible.

Preprint: Astrocytes are increasingly thought to have underestimated important roles in modulating neuronal circuits. Astrocytes in the striatum can regulate dopamine transmission by governing the extracellular tone of axonal neuromodulators. The authors reveal that striatal astrocytes occupy a cell type-specific anatomical and functional relationship with cholinergic interneurons.

Preprint: Depolarization of distal axons is necessary for neurons to translate somatic action potentials into neurotransmitter release. Studies have shown that striatal cholinergic interneurons can drive ectopic action potentials in dopamine (DA) axons and trigger DA release. The authors show that this action occurs within a broader context of axonal signal integration.

The integrated stress response (ISR) is a conserved biochemical pathway that regulates protein synthesis. As such, the ISR is implicated in a wide range of diseases, including brain disorders. In this review, the authors consider the ISR's contribution to brain disorders through the lens of its potential effects on synaptic plasticity.

Preprint: The intricate process of α-synuclein aggregation and fibrillization hold pivotal roles in Parkinson’s disease (PD). While mouse α-synuclein can fibrillate in vitro, whether these fibrils can reproduce structures in the human brain remains unknown. Here the authors report the first atomic structure of mouse α-synuclein fibrils.

Preprint: Recent advances have expanded the role of lipid droplets (LDs) beyond passive lipid storage, implicating their involvement in metabolic processes. Neuronal LDs have been identified in several neural structures, raising questions about their contribution to neurodegenerative disorders. This study outlines an improved methodology to stimulate and isolate mature LDs.

Preprint: The data presented here demonstrates that neurons and their nerve terminals can make use of LDs during electrical activity to provide metabolic support when glucose is in short supply.

Preprint: Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson’s disease (PD). Here, the authors show that VPS13C, a bridge-like lipid transport protein and a PD gene, is a sensor of lysosome stress/damage.

Preprint: Decreased excitability of pyramidal tract neurons in layer 5B (PT5B) of primary motor cortex (M1) has recently been shown in a dopamine-depleted mouse model of parkinsonism. The authors hypothesized that decreased PT5B neuron excitability would disrupt firing patterns of neurons in layer 5 of primary motor cortex.

Preprint: Neurodegenerative disorders have overlapping symptoms and high comorbidity rates, but this is not reflected in overlaps of risk genes. The authors investigated whether ligand-receptor interactions (LRIs) are a mechanism by which distinct genes associated with disease risk can impact overlapping outcomes.

Preprint: Profiling lysosomal content using tag-based lysosomal immunoprecipitation (LysoTagIP) in cell and animal models allowed major discoveries, however studying lysosomal dysfunction in human patients remains challenging. Here, the authors report the development of the tagless LysoIP method to enable rapid enrichment of lysosomes from clinical samples and human cell lines.

Preprint: In Parkinson’s disease (PD), loss of midbrain dopamine neurons is associated with progressive motor and cognitive deficits. Lack of coordination between direct and indirect neurons is implicated in the disease. Here, the authors developed a mouse model of PD/ICD, in which ICD-like behavior was assayed with a delay discounting task.

Preprint: Parkinson’s disease is characterized by the death of substantia nigra (SNc) dopamine (DA) neurons, but the pathophysiological mechanisms that precede and drive their death remain unknown. To address this question, the authors developed a chemogenetic (DREADD) mouse model to increase DA neuron activity, and confirmed this increase using ex vivo electrophysiology.

Preprint: This study leverages X-ray phase-contrast tomography for detailed analysis of neurodegenerative diseases focusing on the 3D visualization and quantification of neuropathological features within fixed human postmortem tissue.

Published: It has been a goal in the field to decode the regulatory logic of an enhancer and to understand the details of how spatiotemporal gene expression is encoded in an enhancer sequence. Here, deep learning models can be used to efficiently design synthetic, cell-type-specific enhancers, starting from random sequences.