Mechanism of human PINK1 activation at the TOM complex in a reconstituted system
By Julia Julia Leonard onPreprint: The authors demonstrate an essential role of the pore-containing subunit TOM40 and its structurally associated subunits TOM7 and TOM22 for PINK1 activation. These molecular findings will aid in the development of small molecule activators of PINK1 as a therapeutic strategy for PD.
Unique functional responses differentially map onto genetic subtypes of dopamine neurons
By savannah onPublished: Genetic strategies to isolate dopaminergic subtypes lead to the establishment of a novel subtype of dopamine neurons within the mouse substantia nigra. The results show that the neural activity patterns of the genetically identified subtypes map to differing features of locomotion, such as acceleration, deceleration, and appetitive. View original preprint.
Astrocytic LRRK2 controls synaptic connectivity through ERM phosphorylation
By savannah onThis work reveals a causal link between the astrocytic and synaptic dysfunction induced by the PD-linked mutation, LRRK2 G2019S, providing a non-cell autonomous mechanism for rescuing aberrant cortical wiring
Sex distribution of GBA1 variant carriers with dementia with Lewy Bodies and Parkinson’s disease
By savannah onSex distribution of GBA1 variant carriers with dementia with Lewy Bodies and Parkinson's disease.
LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology spread
By Emma Sherrell onPublished: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD). This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development. View original preprint.
A topographical atlas of αSyn dosage and cell-type expression in the mouse brain and periphery
By Emma Sherrell onPublished: Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide and presents pathologically with Lewy pathology and dopaminergic neuron loss. This atlas provides much-needed insight into the cellular topography of αSyn, and provides a quantitative map to test assumptions about the role of αSyn in network vulnerability in PD and other αSynucleinopathies. View original preprint.
iATPSnFR2: a high dynamic range fluorescent sensor for monitoring intracellular ATP
By Emma Sherrell onPreprint: Subcellular targeting of the sensor to nerve terminals reveals previously uncharacterized single synapse metabolic signatures, while targeting to the mitochondrial matrix allowed direct quantitative probing of oxidative phosphorylation dynamics.
Phosphoglycerate kinase is a central leverage point in Parkinson’s Disease driven neuronal metabolic deficits
By Emma Sherrell onPreprint: The data indicates that nerve terminal bioenergetic deficits may underly a spectrum of PD susceptibilities and the identification of PGK1 as the limiting enzyme in axonal glycolysis provides a mechanistic underpinning for therapeutic protection.
Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production
By Emma Sherrell onPreprint: The authors'results identify specific metabolic regulators of cellular ATP and ROS balance that may help dissect the roles of these processes in disease and identify therapeutic strategies to independently target energy failure and oxidative stress.
M4-mediated cholinergic transmission is reduced in Parkinsonian mice and its restoration alleviates motor deficits and levodopa-induced dyskinesia
By Emma Sherrell onPreprint: Despite M4-receptors being thought to mediate anti-kinetic effects, restoring M4-receptor function partially rescued Parkinsonian balance and coordination deficits and limited the development of levodopa-induced dyskinetic behaviors, indicating that decreased M4-function contributed to circuit and motor dysfunctions in response to DA loss.
Adaptor protein-3 produces synaptic vesicles that release phasic dopamine
By Emma Sherrell onThe burst firing of midbrain dopamine neurons releases a phasic dopamine signal that mediates reinforcement learning. 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.
Investigation of the genetic aetiology of Lewy body diseases with and without dementia
By Emma Sherrell onPreprint: The authors found that risk alleles rs429358 tagging APOEe4 and rs7668531 near the MMRN1 and SNCA-AS1 genes, increase the odds of developing dementia and that an intronic variant rs17442721 tagging LRRK2 G2019S, on chromosome 12 is protective against dementia. These results should be validated in autopsy confirmed cases in future studies.
UniProtExtractR: an app and R package for easily extracting protein-specific UniProtKB information and fine-tuning organelle resolution
By Emma Sherrell onThe app features interactive frequency tables that globally summarize both the original UniProtKB input query as well as the extracted/changed entry values. Moreover, UniProtExtractR includes a tractable mapping algorithm to define custom organelle-level resolution.
Proteome census upon nutrient stress reveals Golgiphagy membrane receptors
By Emma Sherrell onDuring nutrient stress, macroautophagy is employed to degrade cellular macromolecules, thereby providing biosynthetic building blocks while simultaneously remodeling the proteome. The authors' results, available via an interactive web tool, reveal that autophagic turnover prioritizes membrane-bound organelles (principally Golgi and ER) for proteome remodeling during nutrient stress.
Structural pathway for class III PI 3-kinase activation by the myristoylated GTP-binding pseudokinase VPS15
By Emma Sherrell onPreprint: The class III phosphatidylinositol (PI) 3-kinase complexes I and II (PI3KC3-C1 and -C2) are central to the initiation of macroautophagy and endosomal maturation, respectively. These results provide a pathway of general mechanism for PI3KC3 activation in autophagy and endosome biogenesis and a roadmap for their pharmacological upregulation.
Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD
By Emma Sherrell onPreprint: The authors'results thus define NAP1 and SINTBAD as cargo receptor rheostats, elevating the threshold for mitophagy initiation by OPTN while promoting the progression of the pathway once set in motion by supporting NDP52. These findings shed light on the cellular strategy to prevent pathway hyperactivity while still ensuring efficient progression.
Reduction of a-synuclein aggregates by PIKfyve inhibition via TFEB-mediated lysosomal biogenesis in a Parkinson’s disease model
By Emma Sherrell onPreprint: In the present study, the authors exploited the SH-SY5Y cell model overexpressing a pro-aggregation form of alpha-synuclein to investigate the efficacy of PIKfyve-mediated lysosomal biogenesis, through TFEB, as a potential target for Parkinson's therapy.
Biochemical consequences of glucocerebrosidase 1 mutations in Parkinson’s disease
By Emma Sherrell onPerspective on the biochemical consequences of glucocerebrosidase 1 mutations in Parkinson’s disease.
Dopaminergic denervation and associated MRI microstructural changes in the nigrostriatal projection in early Parkinson’s disease patients
By Emma Sherrell onThe asymmetry between striatal and SNc changes for both dopaminergic depletion and microstructural degeneration biomarkers are consistent with a neurodegenerative process that begins in the striatal terminals before progressing toward the cell bodies in the SNc.
Single-cell somatic copy number variants in brain using different amplification methods and reference genomes
By Emma Sherrell onThis study demonstrates that the authors' semi-automated protocol is suitable for shotgun metagenomic analysis, by significantly producing higher DNA fragment sizes while allowing for improved sample treatment logistics with reduced technical variability and without compromising the structure of the oral microbiome.