Loss of tau expression attenuates neurodegeneration associated with α-synucleinopathy
By savannah onPublication: The role of tau in the development of αS pathology and subsequent neuronal dysfunction has been controversial. Herein, the authors examine the role of tau in the onset and progression of αS pathology using a transgenic mouse model of α-synucleinopathy lacking mouse tau expression. View original preprint.
Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation
By savannah onPublication: In this study, the lipid membrane composition of fibroblasts isolated from control subjects, patients with idiopathic Parkinson's disease and Parkinson's disease patients carrying the L444P GBA mutation (PD-GBA) was assayed using shotgun lipidomics. Findings suggest that L44P GBA mutations have a distinctly altered membrane lipid profile. View original preprint.
Motor learning selectively strengthens cortical and striatal synapses of motor engram neurons
By savannah onPublication: Learning and consolidating new motor skills require plasticity in the motor cortex and striatum, two key motor regions of the brain. However, how neurons undergo synaptic changes and become recruited during motor learning to form a memory remains unknown. Here the authors identify M1 engram neurons important for memory.
A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice
By savannah onPublication: The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, although mechanisms of gut-brain interactions remain incompletely defined. Here, the authors investigated whether a fiber-rich diet influences microglial function in α-synuclein overexpressing (ASO) mice, a preclinical model with PD-like symptoms and pathology. View original preprint.
R1441C and G2019S LRRK2 knock-in mice have distinct striatal molecular, physiological, and behavioral alterations
By savannah onPublication: LRRK2 mutations are closely associated with PD. Convergent evidence suggests that LRRK2 regulates striatal function. Here, by using knock-in mouse lines expressing the two most common LRRK2 pathogenic mutations – G2019S and R1441C – the authors investigated how LRRK2 mutations altered striatal physiology. View original preprint.
Regulatory imbalance between LRRK2 kinase, PPM1H phosphatase, and ARF6 GTPase disrupts the axonal transport of autophagosomes
By savannah onPreprint: Gain-of-function mutations in the LRRK2 gene cause Parkinson's disease (PD), increasing phosphorylation of RAB GTPases through hyperactive kinase activity. The authors found that LRRK2-hyperphosphorylated RABs disrupt the axonal transport of autophagosomes by perturbing the coordinated regulation of cytoplasmic dynein and kinesin motors.
Genome-wide Analysis of Motor Progression in Parkinson Disease
By savannah onPublished: In this article, the authors explored whether there are genetic variants that explain variability in the motor progression found in Parkinson’s in clinical cohorts. They performed a large study genome scan looking at the influence of genetic variation on motor progression and the worsening of motor capabilities among thousands of Parkinson's patients. View original preprint.
Pseudogenes limit the identification of novel common transcripts generated by their parent genes
By savannah onPreprint: Genetic analyses are often complicated by genomic sequences with high sequence similarity. Here, the authors examined the role of pseudogenes on transcriptomic analyses using GB1 and GBAP1 as examples.
Detection of mosaic and population-level structural variants with Sniffles2
By savannah onPublished: The authors developed Sniffles2, a faster and more accurate method to analyze long-ready structural variation calling. This method also solves the problem of family to population-level SV calling to produce fully genotyped VCF files. View original preprint.
Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease
By savannah onPublished: The authors explored the role of resident macrophages in alpha-synuclein-mediated neuroinflammation. They found that border-associated macrophages (BAMs) play a key role in alpha-synuclein induced neuroinflammation where BAMs play a role in immune cell recruitment, infiltration, and antigen presentation. View original preprint.
Distinct adaptations revealed by unbiased proteomic analysis of autophagy cargos in the brain in PINK1 and LRRK2 models of Parkinson’s disease
By savannah onPreprint: Evidence suggests that disruption of autophagy may contribute to PD pathogenesis. Yet, the role it plays is unresolved. The authors used unbiased proteomics to compare basal autophagy to autophagy in two PD-relevant mouse models (PINK1 KO and LRRK2 G2019S). They found different compensatory mechanisms to maintain cellular homeostasis when autophagy is disrupted.
Protein aggregation and calcium dysregulation are the earliest hallmarks of synucleinopathy in human midbrain dopaminergic neurons
By savannah onPreprint: Mutations in the SNCA gene causes PD and aggregates of alpha-synuclein are well known to be present in PD pathology. However, understanding the cellular sequence of events that occurs from mutation to pathology is unresolved. The authors find the temporal sequence of pathophysiological events that occur during neuronal differentiation that likely cause synucleopathies.
Ca2+ channels couple spiking to mitochondrial metabolism in substantia nigra dopaminergic neurons
By savannah onPublished: The authors explore how cellular energy production and demand are matched. By studying the pacemaking activity of dopaminergic neurons using a combination of electrophysiolocal, optical, and molecular method, they found that spike- activated calcium ion entry triggered calcium ion release from the ER, causing mitochondrial oxidative phosphorylation to occur through two calcium-dependent mechanisms.
Mitoguardin-2–mediated lipid transfer preserves mitochondrial morphology and lipid droplet formation
By savannah onPublished: Lipid transport at membrane contact sites is a critical biological process. The authors identify mitoguardin-2, a mitochondrial protein that functions as a lipid transporter at contact sites between the ER and/or lipid droplets. They show that mitoguardin-2 transfers glycerophospholipids between membranes in vitro.
Endoplasmic Reticulum Membrane Contact Sites, Lipid Transport, and Neurodegeneration
By quincy.tichenor onReview: Several mutations of genes that encode proteins localized at the endoplasmic reticulum membrane contact sites result in familial neurodegenerative diseases. Here, the authors provide an overview of such diseases, with a specific focus on proteins that directly or indirectly impact lipid transport.
Neuronal hyperactivity–induced oxidant stress promotes in vivo α-synuclein brain spreading
By quincy.tichenor onPublished: This study investigated the relationship between neuronal activity and interneuronal transfer of α-synuclein, a Parkinson-associated protein, and elucidated mechanisms underlying this relationship.
Genetic variations in GBA1 and LRRK2 genes: Biochemical and clinical consequences in Parkinson disease
By quincy.tichenor onReview: This review compares GBA1 and LRRK2-associated PD, and highlights possible genotype-phenotype associations for GBA1 and LRRK2 separately, based on biochemical consequences of single variants.
“LRRK2 phosphorylation of Rab GTPases in Parkinson’s disease”
By quincy.tichenor onReview: This paper highlights new findings related to LRRK2-mediated phosphorylation of Rab GTPases and their consequences.
Mechanisms controlling selective elimination of damaged lysosomes
By quincy.tichenor onReview: This review discusses the current state of our understanding of mechanisms used to mark and eliminate damaged lysosomes, and discuss the complexities of galectin function and ubiquitin-chain linkage types. Authors also discuss the limitations of available data and challenges with the goal of understanding the mechanistic basis of key steps in lysophagic flux.
P5B-ATPases in the mammalian polyamine transport system and their role in disease
By quincy.tichenor onReview: This review brings together the current knowledge of the cellular function of the mammalian polyamine transport system, focusing on the role of P5B-ATPases ATP13A2-5.