Article Archive

Preprint: Parkinson’s disease (PD) is the second most common neurodegenerative disorder and lacks disease-modifying therapies. The authors developed a Drosophila model for identifying novel glial-based therapeutic targets for PD.

Published: Neuromodulation such as deep brain stimulation (DBS) is advancing as a clinical intervention in neurological and neuropsychiatric disorders, including Parkinson's disease. Here, the authors review current literature in the pre-clinical research fields.

Preprint: Recent studies have demonstrated the importance of extrastriatal dopamine release in motor deficits of Parkinson’s disease (PD). To 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.

Preprint: Mutations in LRRK2 and PINK1 are associated with familial Parkinson's disease (PD). The present study indicates that LRRK2 activation or loss of PINK1 function along parallel pathways impairs ciliogenesis, suggesting a convergent mechanism toward PD.

Preprint: The authors developed an optimized pipeline for single-nuclear RNA sequencing (snRNA-seq) and generated a high-resolution hierarchically organized map revealing 20 molecularly distinct DA neuron subtypes. The data revealed heterogeneity even within neuroanatomical sub-structures. Finally, in a preclinical LRRK2G2019S knock-in mouse model of PD, subtype organization and proportions are preserved.

Publication: The study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases. View original preprint.

Extinction learning is an essential form of cognitive flexibility, which enables obsolete reward associations to be discarded. Here, the team examines the causal relationship of circuit elements to extinction and preservation.

This review covers recent conceptual advances in our basic understanding of the dopamine system – including our rapidly advancing knowledge of dopamine neuron heterogeneity – with special attention to their importance for understanding PD.

This review summarizes previous work characterizing neurotransmitter co-release from dopamine neurons, work examining potential changes in co-release dynamics that result in animal models of Parkinson's disease, and future opportunities for determining how dysfunction in co-release may contribute to circuit dysfunction in Parkinson's disease.

The pathogenesis of degeneration in Parkinson's disease (PD) remains poorly understood but multiple lines of evidence have converged on the presynaptic protein α-synuclein (αsyn). αSyn regulates several cellular processes, however, its normal function remains poorly understood. In this review, the authors focus on its role in exocytosis.

Here, the authors focus on evidence that the activity of dopamine neurons is altered in Parkinson's disease (PD), either as a compensatory response to degeneration or as a result of circuit dynamics or pathologic proteins, based on available human data and studies in animal models of PD.

Using a library of membrane-active polymers the authors have developed a platform for the high-throughput analysis of the membrane proteome. The platform enables near-complete spatially resolved extraction of target membrane proteins directly from their endogenous membranes into native nanodiscs that maintain the local membrane context.

Recent studies in humans with PD and in animal models of the disease have accumulated evidence suggesting that the involvement of the cerebral cortex is complicated. In this review, the authors discuss PD-related changes in frontal cortical motor regions, focusing on neuropathology, changes in neurotransmission, and altered network interactions.

Inducible pluripotent stem cells (iPSCs) derived from patient samples have significantly enhanced our ability to model neurological diseases. Comparative studies of dopaminergic neurons differentiated from iPSCs derived from siblings with Gaucher disease discordant for parkinsonism provide an avenue to explore genetic modifiers contributing to GBA1-associated parkinsonism in disease-relevant cells.

The authors investigated the effects of individual familial PD mutations by developing a medium-throughput platform using genome editing to install individual PD mutations in human pluripotent stem cells (hPSCs) that the authors subsequently differentiated into midbrain lineage cells that include dopaminergic (DA) neurons. Analysis revealed that PD mutations increase pre-mRNA splicing changes.

Not all persons with PD have a dysbiotic microbiome, and not all dysbiotic PD microbiomes have the same features. The authors have developed an intuitive and easily modifiable method to identify the optimal candidates for microbiome-based clinical trials, and subsequently, for treatments that are personalized for each individual's dysbiotic features.

The relative distributions and proportions of neurotransmitter-defined cell types across VTA and SNc have remained unclear. The data shown here complement recent single-cell RNAseq studies and support a more diverse landscape of neurotransmitter-defined cell types in VTA and SNc.

Neuronal insulin resistance is linked to the pathogenesis of Parkinson's disease through unclear, but potentially targetable, mechanisms. The authors delineated neuronal and glial mechanisms of insulin resistance and glucagon-like 1 peptide (GLP-1) receptor agonism in human iPSC models of synucleinopathy.

The degeneration of dopamine neurons in the ventral midbrain is linked to the development of motor symptoms in Parkinson's disease (PD). Evidence suggests that neuroinflammation and mitochondrial dysfunction drive neurodegenerative mechanisms in PD. Results provide evidence for mitochondrial-specific CD8+ T cell infiltration in the brain in driving PD-like pathology.