The lipid flippase ATP10B enables cellular lipid uptake under stress conditions
By savannah onPublished: The authors' data shows that the endo-/lysosomal lipid flippase ATP10B contributes to cellular PC uptake under specific cell stress conditions. View original preprint.
ATG9 vesicles comprise the seed membrane of mammalian autophagosomes
By savannah onThe ratios of ATG9 and LC3-II at different stages of maturation demonstrate that ATG9 proteins are not continuously integrated, but rather are present on the seed vesicles only and become diluted in the expanding autophagosome membrane.
Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex
By savannah onThe presence of PI3KC3-C1 induces a rearrangement of ULK1C from a FIP200:ATG13:ULK1 2:1:1 to a 2:2:2 stoichiometry by dislocating an ATG13 loop from an inhibitory site on the dimeric FIP200 scaffold. This suggests a mechanism for the initiation of autophagy through PI3KC3-C1-induced dimerization of ULK1 as bound to FIP200, followed by an activating trans-autophosphorylation of ULK1.
Basal ganglia neurons in healthy and Parkinsonian primates generate recurring sequences of spikes
By savannah onThe authors conclude that basal ganglia neurons fire in recognizable sequences of ISIs, whose incidence is influenced by the induction of parkinsonism.
Impact of the dopamine system on long-term cognitive impairment in Parkinson’s disease: An exploratory study
By savannah onThe study provides preliminary evidence that alterations in the dopamine system predict the development of clinically-relevant, cognitive impairment in Parkinson’s disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course.
Urinary bis(monacylglycerol) phosphate (BMP) levels are higher in LRRK2 and GBA1 variant carriers but do not predict disease progression in PPMI cohorts
By savannah onThese data support the utility of BMP as a target modulation biomarker in therapeutic trials of genetic and sPD but not as a prognostic or disease progression biomarker.
Updated percentiles for the University of Pennsylvania Smell Identification Test in adults 50 years of age and older
By savannah onThe objective was to develop updated percentiles, based on substantially larger samples than previous norms, to more finely discriminate age- and sex-specific University of Pennsylvania Smell Identification Test (UPSIT) performance among ≥50-year-old adults who may be candidates for studies of prodromal neurodegenerative diseases.
Single-cell spatial transcriptomic and translatomic profiling of dopaminergic neurons in health, aging, and disease
By savannah onPublished: The authors used two approaches to ask which genes are expressed during aging in dopaminergic neurons; the cell type affected in Parkinson's disease. View original preprint.
Early deficits in an in vitro striatal microcircuit model carrying the Parkinson’s GBA-N370S mutation
By savannah onPublished: The results highlight the unique utility of modeling striatal neurons in a modular and highly physiological circuit, which is essential to reveal mechanistic insights of the loss of electrical functional integrity in the striata of GBA1 PD patients. View original preprint.
Genome-wide association identified novel etiological insights associated with Parkinson’s disease in African and African admixed populations
By savannah onThe authors perform a comprehensive genome-wide assessment of PD in African and African admixed ancestry, characterizing population-specific risk, differential haplotype structure and admixture, coding, structural genetic variation, and polygenic risk profiling. The authors identified a novel common risk factor for PD and age at onset at the GBA1 locus, that was found to be rare in non-African/African admixed populations.
Role of autophagy pathway in Parkinson’s disease and related genetic neurological disorders
By savannah onThe authors provide a comprehensive overview of the general importance of autophagy in Parkinson’s disease (PD) and related disorders of the central nervous system (CNS). This reveals a critical link between autophagy and neurodegenerative and neurodevelopmental disorders and suggests that strategies to modulate mitophagy may have greater relevance in the CNS beyond PD.
Targeting the GBA1 pathway to slow Parkinson’s disease: Insights into clinical aspects, pathogenic mechanisms, and new therapeutic avenues
By savannah onTreatments that target the GBA1 pathway could reverse these pathological processes and halt/slow the progression of PD. Ranges from augmentation of GCase activity via GBA1 gene therapy, restoration of normal intracellular GCase trafficking via molecular chaperones, and substrate reduction therapy. This review discusses the pathways associated with GBA1-PD and GBA1-targeted interventions for PD treatment.
LINE-1 retrotransposons drive human neuronal transcriptome complexity and functional diversification
By savannah onPublished: CRISPRi-silencing of LINC01876 results in reduced size of cerebral organoids and premature differentiation of neural progenitors, implicating L1s in human-specific developmental processes. In summary, the authors’ results demonstrate that L1-derived transcripts provide a previously undescribed layer of primate- and human-specific transcriptome complexity that contributes to the functional diversification of the human brain. View original preprint.
Splicing accuracy varies across human introns, tissues, and age
By savannah onThis in-depth characterization of mis-splicing can have important implications for our understanding of the role of splicing inaccuracies in human disease and the interpretation of long-read RNA-sequencing data.
Advances in AAV technology for delivering genetically encoded cargo to the nonhuman primate nervous system
By savannah onModern neuroscience approaches including optogenetics, calcium imaging, and other genetic manipulations have facilitated our ability to dissect specific circuits in rodent models to study their role in neurological disease. These approaches regularly use viral vectors to deliver genetic cargo (e.g., opsins) to specific tissues and genetically engineered rodents to achieve cell-type specificity.
PARK15/FBXO7 is dispensable for PINK1/Parkin-dependent mitophagy in iNeuron and HeLa cell systems
By savannah onThe protein kinase PINK1 and ubiquitin ligase Parkin promote removal of damaged mitochondria via a feed- forward mechanism involving ubiquitin (Ub) phosphorylation (pUb), Parkin activation, and ubiquitylation of mitochondrial outer membrane proteins to support recruitment of mitophagy receptors.
Who is at risk of Parkinson’s disease? Refining the preclinical phase of GBA1 and LRRK2 variant carriers: a clinical, biochemical, and imaging approach
By savannah onGenetic variants in GBA1 and LRRK2 genes are the commonest genetic risk factor for Parkinson’s disease (PD); however, the preclinical profile of GBA1 and LRRK2 variant carriers who will develop PD is unclear. This review aims to highlight the more sensitive markers that can stratify PD risk in non-manifesting GBA1 and LRRK2 variant carriers.
LRRK2-G2019S synergizes with aging and low-grade inflammation to promote gut and peripheral immune cell activation that precede nigrostriatal degeneration
By savannah onOur study suggests an early role of the peripheral immune system and the gut in LRRK2 PD and provides a novel model to study early therapeutic immune targets and biomarkers.
Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at 16q11.2 and MAPT H1 loci
By savannah onThese results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration.
Impaired dopamine release in Parkinson’s disease
By savannah onEvidence indicates that impaired dopamine release can result from disruption to a diverse range of Parkinson’s disease-associated genetic and molecular disturbances, and can be considered as a potential pathophysiological hallmark of Parkinson’s disease.
