Tagless LysoIP method for molecular profiling of lysosomal content in clinical samples
By Emma Sherrell onPreprint: 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.
Inhibition of indirect pathway activity causes abnormal decision-making in a mouse model of impulse control disorder in Parkinson’s disease
By Emma Sherrell onPreprint: 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.
Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration
By Emma Sherrell onPreprint: 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.
3D imaging of neuronal inclusions and protein aggregates in human neurodegeneration by multiscale X-ray phase-contrast tomography
By Emma Sherrell onPreprint: 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.
Cell-type-directed design of synthetic enhancers
By Emma Sherrell onPublished: 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.
Genetic screening and metabolomics identify glial adenosine metabolism as a therapeutic target in Parkinson’s disease
By Emma Sherrell onPreprint: 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.
Concerning neuromodulation as treatment of neurological and neuropsychiatric disorder: Insights gained from selective targeting of the subthalamic nucleus, para-subthalamic nucleus, and zona incerta in rodents
By Emma Sherrell onPublished: 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.
Tonic dendritic GABA release by substantia nigra dopaminergic neurons
By Emma Sherrell onPreprint: 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.
Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain
By Emma Sherrell onPreprint: 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.
Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson’s disease
By Emma Sherrell onPreprint: 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.
Adult-onset deletion of ATP13A2 in mice induces progressive nigrostriatal pathway dopaminergic degeneration and lysosomal abnormalities
By Emma Sherrell onPreprint: 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.
Reward perseveration is shaped by GABAA-mediated dopamine pauses
By Emma Sherrell onExtinction 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.
Polygenic Parkinson’s disease genetic risk score as risk modifier of Parkinsonism in Gaucher disease
By savannah onBiallelic pathogenic variants in GBA1 cause Gaucher disease type 1 (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase, that is associated with increased risk for Parkinson's disease (PD). The objective of this study was to investigate the contribution of PD risk variants to risk for PD in patients with GD1.
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.