Urinary bis(monacylglycerol) phosphate (BMP) levels are higher in LRRK2 and GBA1 variant carriers but do not predict disease progression in PPMI cohortson
These 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 olderon
The 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 diseaseon
These datasets (accessible at spatialbrain.org) represent an invaluable resource for the investigation into spatially governed gene expression in brain cells in health, aging, and disease.
Early striatal hyperexcitability in an in vitro human striatal microcircuit model carrying the Parkinson’s GBA-N370S mutationon
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.
Genome-wide association identified novel etiological insights associated with Parkinson’s disease in African and African admixed populationson
The 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.
The 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 avenueson
Treatments 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.
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.
This 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 systemon
Modern 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.
The 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 approachon
Genetic 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 degenerationon
Our 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 locion
These results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration.
Evidence 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.
The secretion of endogenous α-syn mediated by DNAJC5 is also found in a human neuroblastoma cell line, SH-SY5Y, differentiated into neurons in the presence of retinoic acid, and in human-induced pluripotent stem cell-derived midbrain dopamine neurons. We propose that DNAJC5 forms a palmitoylated oligomer to accommodate and export α-syn.
Assessment of heterogeneity and disease onset in the Parkinson’s Progression Markers Initiative (PPMI) cohort using the α-synuclein seed amplification assay: a cross-sectional studyon
Our results demonstrate that the assay classifies PD patients with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals prior to diagnosis. These findings suggest a crucial role for αSyn-SAA in therapeutic development, both to identify pathologically defined subgroups of PD patients and to establish biomarker-defined at-risk cohorts.
By normalizing the open science and compliance process across funding bodies, we hope to simplify and streamline researcher, institutional, and funder workflows, allowing researchers to focus on science by easily leveraging resources and building upon the work of others.
Our data support a model in which Rab12 binding to a new site in the LRRK2 Armadillo domain activates LRRK2 kinase for Rab phosphorylation and could serve as a new therapeutic target for a novel class of LRRK2 inhibitors that do not target the kinase domain.
Glucocerebrosidase, a Parkinson´s disease-associated protein, is imported into mitochondria and regulates complex I assembly and functionon
Glucocerebrosidase, a Parkinson´s disease-associated protein, is imported into mitochondria and regulates complex I assembly and function. Collection of protocols for paper: "Glucocerebrosidase, a Parkinson´s disease-associated protein, is imported into mitochondria and regulates complex I assembly and function."