Dopamine across timescales and cell types: Relevance for phenotypes in Parkinson’s disease progression
By Emma Sherrell onThis 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.
Alterations in neurotransmitter co-release in Parkinson’s disease
By Emma Sherrell onThis 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 role of α-synuclein in exocytosis
By Emma Sherrell onThe 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.
Role of dopamine neuron activity in Parkinson’s disease pathophysiology
By Emma Sherrell onHere, 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.
A proteome-wide quantitative platform for nanoscale spatially resolved extraction of membrane proteins into native nanodiscs
By Emma Sherrell onUsing 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.
Dysfunction of motor cortices in Parkinson’s disease
By Emma Sherrell onRecent 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.
Comparative study of enriched dopaminergic neurons from siblings with Gaucher disease discordant for parkinsonism
By Emma Sherrell onInducible 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.
Comparison of alternative pre-mRNA splicing and gene expression patterns in midbrain lineage cells carrying familial Parkinson’s disease mutations
By Emma Sherrell onThe 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.
Microbiome-based biomarkers to guide personalized microbiome-based therapies for Parkinson’s disease
By Emma Sherrell onNot 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.
Proportion and distribution of neurotransmitter-defined cell types in the ventral tegmental area and substantia nigra pars compacta
By Emma Sherrell onThe 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.
GLP-1 receptor agonism ameliorates Parkinson’s disease through 1 modulation of neuronal insulin signalling and glial suppression
By Emma Sherrell onNeuronal 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.
Adoptive transfer of mitochondrial antigen-specific CD8+ T-cells in mice causes parkinsonism and compromises the dopamine system
By Emma Sherrell onThe 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.
LRRK2 G2019S mutation suppresses differentiation of Th9 and Treg cells via JAK/STAT3
By Emma Sherrell onThe Leucine-rich repeat kinase-2 (LRRK2) G2019S mutation is one of the well-recognized genetic risk factors in Parkinson's disease (PD). Increased LRRK2 activity was also observed in immune cells from PD patients. The authors generated and characterized a new T cell receptor (TCR) transgenic mouse strain bearing LRRK2 G2019S knock-in mutation.
Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies
By Emma Sherrell onConventional genetic analyses are underpowered to address whether neurodegenerative diseases linked to misfolding of the same protein share genetic risk drivers or whether different protein-aggregation pathologies in neurodegeneration are mechanistically related. The authors study patients based on protein aggregation phenotype to detect variants in a targeted set of genes.
Alpha-synuclein aggregates trigger anti-viral immune pathways and RNA editing in human astrocytes
By Emma Sherrell onParkinson's disease is a neurodegenerative disease characterized by a proteinopathy with marked astrogliosis. To investigate how a proteinopathy may induce a reactive astrocyte state, and the consequence of reactive astrocytic states on neurons, the authors generated hiPSC-derived astrocytes, neurons, and co-cultures and exposed them to small soluble alpha-synuclein aggregates.
Dopamine neuron activity encodes the length of upcoming contralateral movement sequences
By Emma Sherrell onThe relationship between the activity of dopaminergic neurons (DANs) and the length of movement sequences is unknown. The authors imaged the activity of SNc DANs in mice. Results indicate that movement-initiation DANs encode more than a general motivation signal and invigorate aspects of contralateral movements. View original preprint.
Oncogenic BRAF V600E induces glial proliferation through ERK and neuronal death through JNK
By Emma Sherrell onActivating V600E in BRAF is a common driver mutation in cancers of multiple tissue origins. BRAF V600E has also been implicated in neurodegeneration. The present study aims to characterize BRAF V600E on cell death and survival in three major cell types of the CNS: neurons, astrocytes, and microglia.
Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging
By Emma Sherrell onAβ peptides derived from the amyloid precursor protein (APP) have been implicated in the pathogenesis of Alzheimer’s disease. However, the normal function of APP is less clear. Results demonstrate a conserved role for APP in controlling age-dependent proteostasis with plausible relevance to Alzheimer’s disease.
Modeling gene-environment interactions in Parkinson’s disease: Helicobacter pylori infection of Pink1-/- mice induces CD8 T cell-dependent motor and cognitive dysfunction
By Emma Sherrell onParkinson's disease (PD) is a neurodegenerative disorder characterized by loss of motor function. Using a mouse model, the authors demonstrate that infection with Helicobacter pylori leads to the development of motor and cognitive signs.
Large-scale visualization of α-synuclein oligomers in Parkinson’s disease brain tissue
By Emma Sherrell onParkinson’s disease is a neurodegenerative condition characterized by large intraneuronal aggregates in the brain. It has been hypothesized that these large aggregates may form from smaller soluble protein assemblies, often termed oligomers. ASA-PD, is a new imaging method to generate large-scale α-synuclein oligomer maps in post-mortem human brain tissue.