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.
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.
Multi-ancestry genome-wide meta-analysis in Parkinson’s disease
By quincy.tichenor onPublished: The authors performed the first large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases, and 2,458,063 controls, including individuals of European, East Asian, Latin American, and African ancestry. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations. View original preprint.
Membrane remodeling properties of the Parkinson’s disease protein LRRK2
By quincy.tichenor onPreprint: The authors examine how purified LRRK2 directly binds acidic lipid bilayers in a cell-free system and can deform them into narrow tubules in a guanylnucleotide-dependent but ATP-independent way.
Cellular senescence: a key therapeutic target in aging and diseases
By quincy.tichenor onReview: This review discusses the role of SnCs in aging and age-related diseases, strategies to target SnCs, approaches to discover and develop senotherapeutics, and preclinical and clinical advances of senolytics.
Disruption of lysosomal proteolysis in astrocytes facilitates midbrain proteostasis failure in an early-onset PD model
By quincy.tichenor onPublished: Accumulation of advanced glycation end products (AGEs) on biopolymers accompany cellular aging and drives poorly understood disease processes. Here, authors studied how AGEs contribute to development of early on-set Parkinson’s disease (PD) caused by loss-of-function of DJ1, a protein deglycase. View original preprint.
A Markov random field model-based approach for differentially expressed gene detection from single-cell RNA-seq data
By Blythe Lloyd onThe MARBLES, a Markov Random Field model-based approach for differentially expressed gene detection from scRNA-seq data can capture cell-type relationships and account for sample variation by modeling cell-type-specific pseudobulk data. The authors used simulation results to compare this approach to existing methods from two scRNA-seq datasets.
Mechanisms underlying ubiquitin-driven selective mitochondrial and bacterial autophagy
By Blythe Lloyd onReview: The authors review recent efforts to understand the biochemical mechanisms and principles by which cargo are marked with ubiquitin and how ubiquitin-binding cargo receptors use conserved structural modules to recruit the autophagosome initiation machinery, with a particular focus on mitochondria and intracellular bacteria as cargo.
GBA Variants and Parkinson Disease: Mechanisms and Treatments
By Blythe Lloyd onReview: The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase). Around 5–15% of PD patients have mutations in the GBA gene. This review discusses the pathways associated with GBA-PD and highlights potential treatments which may act to target GCase and prevent neurodegeneration.
Lyso-IP: Uncovering Pathogenic Mechanisms of Lysosomal Dysfunction
By Blythe Lloyd onReview: The development of the Lyso-IP approach and similar methods now allow for lysosomal purification within ten minutes. This review discusses the impact of this new methodology in uncovering the role of lysosomes in neurodegenerative conditions.