Article Archive

Published: The authors developed an assay, Endo-IP, to rapidly isolate early and sorting endosomes. Using this method, they found a unique proteomic landscape of early/sorting endosomes, distinct from lysosomal proteomic landscape. Combining Endo-IP and Lyso-IP, the authors provided a spatial digital snapshot of amyloid-beta products. View original preprint.

Published: Parkinson's disease likely reflects a complex interaction among genetic and environmental factors. Here, the role of nicotine, SV2 and the alpha-synuclein were examined. The study suggests that SV2 may be needed for the protection nicotine provides from Parkinson's-related neurotoxicity. View original preprint.

Preprint: Analysis of local genetic correlations can identify genomic regions that associate with more than one trait which can provide a better mechanistic understanding of disease. The authors identified several local genetic correlations between common neurodegenerative and neuropsychiatric diseases.

Published: Genome-wide association studies have increased our understanding of PD by identifying genetic variants. The authors used a mitophagy screening assay to evaluate the functional significance of these variants and found two new regulators of PINK-dependent mitophagy, KAT8, and KANSL1. View original preprint.

Published: Dementia is an important feature of late-stage PD. The authors used an unbiased, genome-wide approach to identify genetic polymorphisms that associate with faster development of dementia in PD patients. They identified four genetic regions that are associated with progression to dementia in PD, including APOE and three previously unknown regions. View original preprint (https://www.medrxiv.org/content/10.1101/2022.05.23.22275465v1).  

Published: Those living with both PD and type 2 diabetes can present with more severe motor and cognitive symptoms. The authors investigated whether more severe neuroaxonal injury in PD patients was the cause. They confirmed these findings and found these patients had higher serum neurofilament light levels. View original preprint.

Published: Disease progression in PD patients is variable, but blood biomarkers may be useful. The authors evaluated serum neurofilament light (NfL) as a potential prognostic biomarker for PD. They found that serum NfL provided an objective measure of neurodegeneration in PD patients. View original preprint.

Preprint: Genome-wide association studies have identified several risk loci for PD, providing insights into the mechanisms of disease initiation. Previously, the RIMS2 locus was identified as a determinant of dementia in PD. The authors evaluated 2536 individuals evaluated it, but found no association between RIMS2 and development of PD-related dementia.

Published: Auxilin helps in recycling of synaptic vesicles to facilitate neurotransmission and loss of auxilin is associated with PD. The authors show auxilin knockout mice exhibit typical PD pathology, dopamine transport is disrupted due to slower dopamine reuptake kinetics, and that macroautophagy and defective synaptic vesicle sorting contributes to dopamine dyshomeostasis. View original preprint.

Preprint: The authors provide an extensive single cell analysis profiling nearly 80,000 brain nuclei from prefrontal cortex of late-stage Parkinson’s disease brains, demonstrate that α-synuclein pathology is inversely correlated with chaperone expression in excitatory neurons, found a selective abatement of neuron-astrocyte interactions with enhanced neuroinflammation, and augmented the study with proteomic analysis and cross-comparisons with Alzheimer’s disease datasets.

Published: Mutations in synaptojanin 1 (SJ1) and auxilin have been implicated in PD. The authors show that auxilin knockout mice have similar nigrostriatal changes to SJI mutant mice. Furthermore, auxilin/SJ1 double mutant mice have more severe defects and shower lifespans, showing the mutations have a synergistic interaction. View original preprint.

Published: The enteric nervous system shapes the intestinal environment and communicates with various brain organs, including the brain. The authors used recombinant adeno-associated viral (rAAV) vectors and chemogenetics to map and activate enteric neurons in mice with spatial and temporal resolution. View original preprint.

Preprint: The authors describe a novel engineered adeno-associated virus (AAV) variant, AAV.CAP-Mac, that enables systemic, brain-wide gene delivery in infants of two Old World primate species, rhesus macaque and green monkey.

Published: VPS13 proteins form conduits between organelles at contact sites that allow for bulk lipid flow between them. The authors present a crystal structure of how the adaptor binding domain of VPS13 interacts with Pro-X-Pro motifs present in VPS13 receptors at organellar membranes. View original preprint.

Published: The authors show that SHIP164 shares strong structural similarities with VPS13 and ATG2 and, like these two proteins, functions as a lipid transport protein. SHIP164 localizes to clusters of endocytic vesicles and loss of SHIP164 disrupts retrograde traffic of certain organelles to the Golgi complex. View original preprint.

Published: Mutations in VPS13C cause early onset, autosomal recessive PD. VPS13C encodes a lipid transfer protein that is localized to ER-endosome/lysosome contact sites. The authors demonstrate that depletion of VPS13C causes an accumulation of lysosomes and activated STING, suggesting a link between ER-lysosome lipid transfer and innate immune activation. View original preprint.

Published: LRRK2 kinase activating mutations are the most common genetic cause of PD. Rab29, a membrane-anchored GTPase, regulates LRRK2’s kinase activity and brings it to the Golgi. The authors report cryo-EM structures of LRRK2-Rab29 complexes in three oligomeric states illustrating LRRK2 membrane recruitment and activation. View original preprint.

Published: Mutations in PINK1 and Parkin are implicated in PD via abherrant mitophagy. The authors identified ubiquitylated substrates of endogenous Parkin in mouse neurons by proteomic analysis. They identified and validated 22 protein targets of Parkin that are conserved in human neurons providing a functional Parkin landscape in neuronal cells. View original preprint.

Published: Mutations in LRRK2 that cause PD activate its kinase activity. These activating mutations of LRRK2 phosphorylate Rab GTPases. The authors define two binding sites on LRRK2 that deliver it to the surfaces of specific intracellular membranes, and then retain it there after an initial phosphorylation event. View original preprint here.

Published: LRRK2 is a promising candidate for PD therapeutics via reduction of its kinase activity. The authors investigated 98 LRRK2 variants and their effects on function. They found 22 variants that robustly stimulated LRRK2 kinase activity and 12 variants that suppressed microtubule association in the presence of Type 1 kinase inhibitors. View original preprint.