PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems
By onPINK1 and Parkin promote damaged mitochondria removal through Ub phosphorylation, Parkin activation. FBXO7 mutation in PD may not affect mitophagy in HeLa and neuron cells, suggesting it may not play a significant role in Parkin-dependent mitophagy.
Protein aggregation and calcium dysregulation are hallmarks of familial Parkinson’s disease in midbrain dopaminergic neurons
By onMutations in SNCA gene cause PD by forming α-synuclein aggregates. Using hiPSCs, we traced pathophysiological events, revealing early oligomeric aggregate formation, calcium signaling impairments, and multiple cellular stresses leading to cell death.
Golgi-IP, a novel tool for multimodal analysis of Golgi molecular content
By onThe authors develop a method for the rapid capture of intact Golgi via Golgi immunoprecipitation. Using high-resolution mass spectrometry, the approach allows the unbiased characterization of the Golgi proteome, metabolome, and lipidome.
Advances in AAV technology for delivering genetically encoded cargo to the nonhuman primate nervous system
By 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. However, the translatability of these rodent models, cross-species validation of identified targets, and translational efficacy of potential therapeutics in larger animal models like nonhuman primates remains difficult due to the lack of efficient primate viral vectors. A refined understanding of the nonhuman primate nervous system promises to deliver insights that can guide the development of treatments for neurological and neurodegenerative diseases. Here, we outline recent advances in the development of adeno-associated viral vectors for optimized use in nonhuman primates. These tools promise to help open new avenues for study in translational neuroscience and further our understanding of the primate brain.
α-Synuclein Promotes Neuronal Dysfunction and Death by Disrupting the Binding of Ankyrin to β-Spectrin
By onα-Synuclein plays a key role in the pathogenesis of Parkinson's disease and related disorders, but critical interacting partners and molecular mechanisms mediating neurotoxicity are incompletely understood. We show that α-synuclein binds directly to β-spectrin. Using males and females in a Drosophila model of α-synuclein-related disorders, we demonstrate that β-spectrin is critical for α-synuclein neurotoxicity. Further, the ankyrin binding domain of β-spectrin is required for α-synuclein binding and neurotoxicity. A key plasma membrane target of ankyrin, Na+/K+ ATPase, is mislocalized when human α-synuclein is expressed in Drosophila Accordingly, membrane potential is depolarized in α-synuclein transgenic fly brains. We examine the same pathway in human neurons and find that Parkinson's disease patient-derived neurons with a triplication of the α-synuclein locus show disruption of the spectrin cytoskeleton, mislocalization of ankyrin and Na+/K+ ATPase, and membrane potential depolarization. Our findings define a specific molecular mechanism by which elevated levels of α-synuclein in Parkinson's disease and related α-synucleinopathies lead to neuronal dysfunction and death.SIGNIFICANCE STATEMENT The small synaptic vesicle associate protein α-synuclein plays a critical role in the pathogenesis of Parkinson's disease and related disorders, but the disease-relevant binding partners of α-synuclein and proximate pathways critical for neurotoxicity require further definition. We show that α-synuclein binds directly to β-spectrin, a key cytoskeletal protein required for localization of plasma membrane proteins and maintenance of neuronal viability. Binding of α-synuclein to β-spectrin alters the organization of the spectrin-ankyrin complex, which is critical for localization and function of integral membrane proteins, including Na+/K+ ATPase. These finding outline a previously undescribed mechanism of α-synuclein neurotoxicity and thus suggest potential new therapeutic approaches in Parkinson's disease and related disorders
Constitutive nuclear accumulation of endogenous alpha-synuclein in mice causes motor impairment and cortical dysfunction, independent of protein aggregation
By onThe authors created mice in which endogenous a-synuclein is localized to the nucleus. The mice show motor and GI deficits and motor cortex atrophy, suggesting that chronic nuclear a-synuclein can cause toxic phenotypes independent of its aggregation.
An open-source head-fixation and implant-protection system for mice
By onThis study presents a head-fixation and implant-protection system for mice including a headbar, headhat and head fixation station to facilitate experimental procedures in vivo. All 3D-printing files are open source and readily available and editable
CRISPR/Cas9-Based Functional Genomics in Human Induced Pluripotent Stem Cell–Derived Models: Can “the Stars Align” for Neurodegenerative Diseases?
By onThe article discusses the use of CRISPR/Cas9 in studying human diseases using stem cell models, highlighting its potential for advancing functional genomics research.
The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1
By onThe authors identify novel transcripts from both GBA1 and GBAP1, including protein-coding transcripts that are translated in vitro and detected in proteomic data, but that lack GCase activity.
RBG Motif Bridge-Like Lipid Transport Proteins: Structure, Functions, and Open Questions
By onThe life of eukaryotic cells requires the transport of lipids between membranes, which are separated by the aqueous environment of the cytosol. Vesicle-mediated traffic along the secretory and endocytic pathways and lipid transfer proteins (LTPs) cooperate in this transport. Until recently, known LTPs were shown to carry one or a few lipids at a time and were thought to mediate transport by shuttle-like mechanisms. Over the last few years, a new family of LTPs has been discovered that is defined by a repeating β-groove (RBG) rod-like structure with a hydrophobic channel running along their entire length. This structure and the localization of these proteins at membrane contact sites suggest a bridge-like mechanism of lipid transport. Mutations in some of these proteins result in neurodegenerative diseases. Here we review the known properties and well-established or putative physiological roles of these proteins, and we highlight the many questions that remain open about their functions.
Evaluation of an adapted semi-automated DNA extraction for human salivary shotgun metagenomics
By onThis study demonstrates that the authors’ semi-automated protocol is suitable for shotgun metagenomic analysis.
Membrane curvature sensing and stabilization by the autophagic LC3 lipidation machinery
By onDuring autophagy initiation, the curved phagophore is stabilized. Using in vitro reconstitution and MD simulations, authors show that WIPI2 and ATG16L1 bind these curved phagophores and the ATG12-5-16L1 complex is responsible for membrane curvature.
Biomarkers of neurodegeneration and glial activation validated in Alzheimer’s disease assessed in longitudinal cerebrospinal fluid samples of Parkinson’s disease
By onSeveral pathophysiological processes are involved in Parkinson’s disease (PD) and could inform in vivo biomarkers. We assessed an established biomarker panel, validated in Alzheimer’s Disease, in a PD cohort. Except for αSyn, the additional biomarkers did not differentiate PD and HC, and none showed longitudinal differences, but most markers predict cognitive decline in PD during follow-up.
The longitudinal progression of autonomic dysfunction in Parkinson’s disease: a 7-year study
By onAutonomic dysfunction, including gastrointestinal, cardiovascular, and urinary dysfunction, is often present in early Parkinson's Disease (PD). However, the knowledge of the longitudinal progression of these symptoms, and the connection between different autonomic domains, is limited. Using data collected from PPMI, autonomic dysfunction was measured using the Scales for Outcomes in Parkinson's Disease (SCOPA-AUT). Symptom frequency and mean scores over 7 years were determined. At baseline, greater SCOPA-AUT total score was associated with lower UPSIT scores (r = −0.209, p = 0.006) and with greater total MDS-UDPRS III score (r = 0.218, p = 0.004).
KAT8 compound inhibition inhibits the initial steps of PINK1-dependant mitophagy
By onThe authors provide additional support for KAT8 inhibition as a regulator of mitophagy and autophagy processes.
Microbes and Parkinson’s Disease: from associations to mechanisms
By onSeveral microbes, including viruses, bacteria, and fungi, have been associated with an increased risk of PD in humans. Microbial infections can induce similar common pathways that are associated with PD, including systemic inflammatory responses, α-synuclein misfolding, and disruption of mitochondria. PD-associated gene mutations can impact host–microbe interactions, suggesting that even familial forms of PD may be influenced by microbes.
Feed-forward metabotropic signaling by Cav1 Ca2+ channels supports pacemaking in pedunculopontine cholinergic neurons
By onCholinergic neurons (CNs) in the pedunculopontine nucleus (PPN) are lost in the course of Parkinson’s disease. PPN CNs have a distinctive physiological phenotype that shares only some of the features of other selectively vulnerable neurons in PD.
Sphingolipid changes in Parkinson L444P GBAmutation fibroblasts promote α-synuclein aggregation
By onIntraneuronal accumulation of aggregated α-synuclein is a pathological hallmark of Parkinson’s disease. Therefore, mechanisms capable of promoting α-synuclein deposition bear important pathogenetic implications. Mutations of the glucocerebrosidase 1 (GBA) gene represent a prevalent Parkinson’s disease risk factor. They are associated with loss of activity of a key enzyme involved in lipid metabolism, glucocerebrosidase, supporting a mechanistic relationship between abnormal α-synuclein–lipid interactions and the development of Parkinson pathology. 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. The lipid profile of PD-GBA fibroblasts differed significantly from that of control and idiopathic Parkinson’s disease cells. It was characterized by an overall increase in sphingolipid levels. It also featured a significant increase in the proportion of ceramide, sphingomyelin and hexosylceramide molecules with shorter chain length and a decrease in the percentage of longer-chain sphingolipids. The extent of this shift was correlated to the degree of reduction of fibroblast glucocerebrosidase activity. Lipid extracts from control and PD-GBA fibroblasts were added to recombinant α-synuclein solutions. The kinetics of α-synuclein aggregation were significantly accelerated after addition of PD-GBA extracts as compared to control samples. Amyloid fibrils collected at the end of these incubations contained lipids, indicating α-synuclein–lipid co-assembly. Lipids extracted from α-synuclein fibrils were also analysed by shotgun lipidomics. Data revealed that the lipid content of these fibrils was significantly enriched by shorter-chain sphingolipids. In a final set of experiments, control and PD-GBA fibroblasts were incubated in the presence of the small molecule chaperone ambroxol. This treatment restored glucocerebrosidase activity and sphingolipid levels and composition of PD-GBA cells. It also reversed the pro-aggregation effect that lipid extracts from PD-GBA fibroblasts had on α-synuclein. Taken together, the findings of this study indicate that the L444P GBA mutation and consequent enzymatic loss are associated with a distinctly altered membrane lipid profile that provides a biological fingerprint of this mutation in Parkinson fibroblasts. This altered lipid profile could also be an indicator of increased risk for α-synuclein aggregate pathology.
ggtranscript: an R package for the visualization and interpretation of transcript isoforms using ggplot2
By onThe authors present ggtranscript, an R package that provides a fast and flexible method to visualize and compare transcripts from long-read sequences. This tool is an extension of ggplot2.
PKC isoforms activate LRRK1 kinase by phosphorylating conserved residues (Ser1064, Ser1074 and Thr1075) within the CORB GTPase domain
By onLeucine-rich-repeat-kinase 1 (LRRK1) and its homologue LRRK2 are multidomain kinases. Here, the authors study the mechanism controlling LRRK1 activity and reveal a novel unexpected activation mechanism.
