Adaptor protein-3 produces synaptic vesicles that release phasic dopamine
By onThe burst firing of midbrain dopamine neurons releases a phasic dopamine signal that mediates reinforcement learning. At many synapses, however, high firing rates deplete synaptic vesicles (SVs), resulting in synaptic depression that limits release. What accounts for the increased release of dopamine by stimulation at high frequency? We find that adaptor protein-3 (AP-3) and its coat protein VPS41 promote axonal dopamine release by targeting vesicular monoamine transporter VMAT2 to the axon rather than dendrites. AP-3 and VPS41 also produce SVs that respond preferentially to high-frequency stimulation, independent of their role in axonal polarity. In addition, conditional inactivation of VPS41 in dopamine neurons impairs reinforcement learning, and this involves a defect in the frequency dependence of release rather than the amount of dopamine released. Thus, AP-3 and VPS41 promote the axonal polarity of dopamine release but enable learning by producing a distinct population of SVs tuned specifically to high firing frequency that confers the phasic release of dopamine.
Reduced striatal M4-cholinergic signaling following dopamine loss contributes to parkinsonian and l-DOPA–induced dyskinetic behaviors
By onImbalances in dopamine and acetylcholine affect motor function in Parkinson's disease. Contrary to conventional theories, reduced cholinergic transmission at M4 receptors in dopamine-depleted mice alleviated motor deficits and dyskinetic behavior.
Single-cell somatic copy number variants in brain using different amplification methods and reference genomes
By onSomatic mutations in the brain are well-known, requiring single-cell whole genome amplification before sequencing. PicoPLEX, MDA, and PTA whole genome amplification methods were compared on brain nuclei, showing different properties.
LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology spread
By onMutations in LRRK2 are the most common cause of familial Parkinson’s disease. This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a workflow for systematic evaluation of brain-wide phenotypes
Proteome census upon nutrient stress reveals Golgiphagy membrane receptors
By onDuring nutrient stress, macroautophagy is employed to degrade cellular macromolecules. The authors' results reveal that autophagic turnover prioritizes membrane-bound organelles for proteome remodeling during nutrient stress.
Investigation of the genetic aetiology of Lewy body diseases with and without dementia
By onThe authors found that risk alleles rs429358 tagging APOEe4 and rs7668531, increase the odds of developing dementia and that an intronic variant rs17442721 tagging LRRK2 G2019S, on chromosome 12 is protective against dementia.
UniProtExtractR: an app and R package for easily extracting protein-specific UniProtKB information and fine-tuning organelle resolution
By onUniProtExtractR is an app and R package that simplifies extracting protein entry information from UniProtKB, offering interactive tables and custom organelle-level resolution. It is user-friendly and freely accessible online.
Molecular heterogeneity in the substantia nigra: A roadmap for understanding PD motor pathophysiology
By onThis article discusses the existing knowledge of DA neuron subtypes and attempts to provide a roadmap for how their distinctive properties can provide novel insights into the motor symptoms of Parkinson's disease (PD).
Unique functional responses differentially map onto genetic subtypes of dopamine neurons
By onGenetic strategies to isolate dopaminergic subtypes established a novel subtype of dopamine neurons within the mouse substantia nigra. The results show that the subtypes each display different neural activity patterns related to locomotion and reward
Disrupted sleep-wake regulation in the MCI-Park mouse model of Parkinson’s Disease
By onDisrupted sleep has a profound adverse impact on lives of Parkinson's Disease (PD) patients and their caregivers. Sleep disturbances are exceedingly common in PD, with substantial heterogeneity in type, timing, and severity. Among the most common sleep-related symptoms reported by PD patients are insomnia, excessive daytime sleepiness, and sleep fragmentation, characterized by interruptions and decreased continuity of sleep. Alterations in brain wave activity, as measured on the electroencephalogram (EEG), also occur in PD, with changes in the pattern and relative contributions of different frequency bands of the EEG spectrum to overall EEG activity in different vigilance states consistently observed. The mechanisms underlying these PD-associated sleep-wake abnormalities are poorly understood, and they are ineffectively treated by conventional PD therapies. To help fill this gap in knowledge, a new progressive model of PD - the MCI-Park mouse- was studied. Near the transition to the parkinsonian state, these mice exhibited significantly altered sleep-wake regulation, including increased wakefulness, decreased non-rapid eye movement (NREM) sleep, increased sleep fragmentation, reduced rapid eye movement (REM) sleep, and altered EEG activity patterns. These sleep-wake abnormalities mirror those identified in PD patients. Thus, this model may help elucidate the circuit mechanisms underlying sleep disruption in PD and identify targets for novel therapeutic approaches.
LINE-1 retrotransposons drive human neuronal transcriptome complexity and functional diversification
By onThe genetic mechanisms underlying the expansion in size and complexity of the human brain remain poorly understood. Long interspersed nuclear element–1 (L1) retrotransposons are a source of divergent genetic information in hominoid genomes, but their importance in physiological functions and their contribution to human brain evolution are largely unknown. Using multiomics profiling, we here demonstrate that L1 promoters are dynamically active in the developing and the adult human brain. L1s generate hundreds of developmentally regulated and cell type–specific transcripts, many that are co-opted as chimeric transcripts or regulatory RNAs. One L1-derived long noncoding RNA, LINC01876, is a human-specific transcript expressed exclusively during brain development. CRISPR interference silencing of LINC01876 results in reduced size of cerebral organoids and premature differentiation of neural progenitors, implicating L1s in human-specific developmental processes. In summary, our results demonstrate that L1-derived transcripts provide a previously undescribed layer of primate- and human-specific transcriptome complexity that contributes to the functional diversification of the human brain.
A fluid-walled microfluidic platform for human neuron microcircuits and directed axotomy
By onThe authors built a microfluidic device that mimics neuronal circuits and enables drug screening for effects on neuronal connections.
A role for the subthalamic nucleus in aversive learning
By onThe subthalamic nucleus (STN) is critical for behavioral control; its dysregulation consequently correlates with neurological disorders, including PD. To investigate STN and aversion, affective behavior is addressed using optogenetics in mice.
Gut mucosal cells transfer α-synuclein to the vagus nerve
By onPublished: These findings highlight a potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells. View original preprint.
Microbial amyloids in neurodegenerative amyloid diseases
By onPublished: Inhibiting microbial amyloids or their interactions with the host, may therefore represent a tangible target to limit various amyloid pathologies.
Peripheral MC1R Activation Modulates Immune Responses and is Neuroprotective in a Mouse Model of Parkinson’s Disease
By onPreprint: The present study investigates the impact of NDP-MSH, a synthetic melanocortin receptor (MCR) agonist that does not cross BBB, on the immune system and the nigrostriatal dopaminergic system in mouse model of PD.
Rethinking the network determinants of motor disability in Parkinson’s disease
By onFor roughly the last 30 years, the notion that striatal dopamine (DA) depletion was the critical determinant of network pathophysiology underlying the motor symptoms of Parkinson’s disease (PD) has dominated the field. While the basal ganglia circuit model underpinning this hypothesis has been of great heuristic value, the hypothesis itself has never been directly tested. Moreover, studies in the last couple of decades have made it clear that the network model underlying this hypothesis fails to incorporate key features of the basal ganglia, including the fact that DA acts throughout the basal ganglia, not just in the striatum. Underscoring this point, recent work using a progressive mouse model of PD has shown that striatal DA depletion alone is not sufficient to induce parkinsonism and that restoration of extra-striatal DA signaling attenuates parkinsonian motor deficits once they appear. Given the broad array of discoveries in the field, it is time for a new model of the network determinants of motor disability in PD.
Anionic nanoplastic contaminants promote Parkinson’s disease–associated α-synuclein aggregation
By onStudies show nanoplastic pollution can trigger α-synuclein protein fibrils formation and spread in the brain, potentially linking nanoplastics to Parkinson's disease and related dementias.
Central and peripheral innate and adaptive immunity in Parkinson’s disease
By onParkinson’s disease is a chronic inflammatory disorder affecting multiple systems. Innovative immunomodulatory interventions are needed to address central and peripheral immune responses during disease onset and progression.
A leaky gut dysregulates gene networks in the brain associated with immune activation, oxidative stress, and myelination in a mouse model of colitis
By onThe gut and brain are interconnected in human disease. Colitis models show reproducible genetic programs affecting both colon and brain, highlighting immune activation and potential therapeutic targets in the gut-brain axis.
