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.
Vibrational stabilization of complex network systems
By savannah onPublished: Many natural and man-made network systems need to maintain certain patterns, such as working at equilibria or limit cycles, to function properly. The authors provide some numerical results that demonstrate the validity of our theoretical findings.
Parkinson’s genes orchestrate pyroptosis through selective trafficking of mtDNA to leaky lysosomes
By savannah onPreprint: Breach of lysosomes allows mtDNA to access cytosol, requiring multiple Parkinson's disease-related proteins and Gasdermin pores, identified in the screen. These data place mitochondria-to-lysosome transport as a driver of pyroptosis and link multiple PD proteins along a common pathway.
Genetic meta-analysis of levodopa induced dyskinesia in Parkinson’s disease
By savannah onPublished: Based on a functional annotation analysis on chromosome 1, we determined that changes in DNAJB4 gene expression, close to LRP8, are an additional potential cause of increased susceptibility to LiD. Baseline anxiety status was significantly associated with LiD.
Mitochondrial degradation: Mitophagy and beyond
By savannah onPublished: The molecular signals driving varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.
A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy
By savannah onPublished: Structural and functional data support a model in which the TBK1-dependent phosphorylation of RAB7A serves as a switch, promoting mitophagy by relieving Rubicon inhibition and favoring Pacer activation. View original preprint.
Therapeutic potential of PTB inhibition through converting glial cells to neurons in the brain
By savannah onPublished: Multiple lines of evidence suggest that Ptbp1 depletion can convert a selective subpopulation of glial cells into neurons and, via this and other mechanisms, reverse deficits in a Parkinson's disease model, emphasizing the importance of future efforts in exploring this therapeutic strategy.
Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem?
By savannah onPublished: Over 15 FDA approved drugs, numerous ongoing clinical trials, RNA therapeutics, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), have shown potential to treat human disease. RNA therapeutics can be used to treat widespread human disease, the rate-limiting delivery problem of endosomal escape must be solved in a nontoxic manner.