Toward a standard model for autophagosome biogenesis
By Emma Sherrell onTwo papers in this issue resolve a long-standing obstacle to a “standard model” for autophagosome biogenesis in mammals.
The annotation and function of the Parkinson’s and Gaucher disease-linked gene GBA1 has been concealed by its protein-coding pseudogene GBAP1
By Emma Sherrell onHere, the 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.
Central and peripheral innate and adaptive immunity in Parkinson’s disease
By Emma Sherrell onParkinson’s disease (PD) is a multisystem disorder with characteristics of a chronic inflammatory disease. To develop effective immunomodulatory interventions to combat PD, researchers need to think innovatively about the implications of orchestrated central and peripheral innate and adaptive immune responses that occur as the disease begins and progresses.
Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency
By Julia Julia Leonard onNeuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe, and untreatable. The authors recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction.
Loss of primary cilia and dopaminergic neuroprotection in pathogenic LRRK2-driven and idiopathic Parkinson’s disease
By Julia Julia Leonard onActivating LRRK2 mutations causes Parkinson's disease. Previously, work showed that cholinergic interneurons and astrocytes lose primary cilia in LRRK2 mutant mice. Here, the data strongly suggest that loss of cilia in specific striatal cell types decreases neuroprotection for dopamine neurons in mice and human Parkinson's disease.
Open-source platform for kinematic analysis of mouse forelimb movement
By Emma Sherrell onAn open-source behavioral platform and software solution for studying fine motor skills in mice performing reach-to-grasp tasks. The behavioral platform uses readily available and 3D-printed components and was designed to be affordable and universally reproducible.
3D bioprinting of human neural tissues with functional connectivity
By Emma Sherrell onProbing how human neural networks operate is hindered by the lack of reliable human neural tissues amenable to the dynamic functional assessment of neural circuits. Team Scherzer developed a 3D bioprinting platform to assemble tissues with defined human neural cell types in a desired dimension using a commercial bioprinter.
Visualizing chaperone-mediated multistep assembly of the human 20S proteasome
By Emma Sherrell onDedicated assembly factors orchestrate the stepwise production of molecular machines, including the 28-subunit proteasome core particle (CP) that mediates protein degradation. This article presents cryo-EM reconstructions of seven recombinant human subcomplexes that visualize all five chaperones and the three active site propeptides across a wide swath of the assembly pathway.
Polyglucosan body density in the aged mouse hippocampus is controlled by a novel modifier locus on chromosome 1
By Emma Sherrell onAging can be associated with the accumulation of polyglucosan bodies (PGBs). While PGBs have a detrimental effect on cognition, the underlying mechanism and clinical relevance of age-related PGB accumulation remain unknown. Here, the authors investigated the genetic basis and functional impact of age-related PGB accumulation in mice.
Transcriptional programs mediating neuronal toxicity and altered glial-neuronal signaling in a Drosophila knock-in tauopathy model
By Emma Sherrell onMutations in the gene encoding tau cause autosomal dominant forms of frontotemporal dementia. Prior models of frontotemporal dementia replicate features of the disease but do not recreate the genetic context. This article presents a genetic model of tauopathy, which recapitulates the genetic context and phenotypic features of the disease.
Neuronal dysfunction and gene modulation by non-coding RNA in Parkinson’s disease and synucleinopathies
By Julia Julia Leonard onEmerging evidence suggests that non-coding RNAs (ncRNAs) contribute to molecular events underlying progressive neuronal degeneration. This review discusses recent literature focused on the role of RNA-based mechanisms involved in different aspects of neuronal pathology in Parkinson’s disease and synucleinopathy models.
Generation of the iPSC line FINi002-A from a male Parkinson’s disease patient carrying compound heterozygous mutations in the PRKN gene
By Julia Julia Leonard onThis article describes the generation of the iPSC line FINi002-A from a male Parkinson's disease patient carrying compound heterozygous mutations in the PRKN gene.
Alpha-synuclein overexpression can drive microbiome dysbiosis in mice
By Emma Sherrell onGrowing evidence indicates that persons living with Parkinson's disease (PD) have a unique composition of indigenous gut microbes. Here, the authors used a transgenic mouse strain, which overexpress wild-type human α-syn to test how the gut microbiome composition responds in this model of PD pathology during aging.
Fluorescence microscopy shadow imaging for neuroscience
By Emma Sherrell onFluorescence microscopy remains a widely applied experimental approaches in neuroscience and beyond and is continuously evolving to make it easier and more versatile. This review highlights the inherent limitations of fluorescence microscopy and conventional labeling and summarizes the pros and cons of recent shadow imaging approaches.
Generation of locus coeruleus norepinephrine neurons from human pluripotent stem cells
By Julia Julia Leonard onCentral norepinephrine (NE) neurons, located mainly in the locus coeruleus (LC), are implicated in diverse psychiatric and neurodegenerative diseases and are an emerging target for drug discovery. To facilitate their study, the authors developed a method to generate 40–60% human LC-NE neurons from human pluripotent stem cells.
Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease
By savannah onLittle is known about circular RNAs (circRNAs) in specific brain cells and human neuropsychiatric disease. This study shows that circular RNAs in the human brain are tailored to neuron identity and implicate circRNA-regulated synaptic specialization in neuropsychiatric diseases.
Evaluating the performance of polygenic risk profiling across diverse ancestry populations in Parkinson’s disease
By savannah onObjective: This study aims to address disparities in risk prediction by evaluating the performance of polygenic risk score (PRS) models using the 90 risk variants across 78 independent loci previously linked to Parkinson’s disease (PD) risk across seven diverse ancestry populations.
NeuroBooster Array: A genome-wide genotyping platform to study neurological disorders across diverse populations
By Devin Della Maggiora onPreprint: People envisage this valuable tool will standardize genetic studies in neurological disorders across different ancestral groups, allowing researchers to perform genetic research inclusively and at a global scale.
The non-coding GBA1 rs3115534 variant is associated with REM sleep behavior disorder in Nigerians
By Devin Della Maggiora onPreprint: The authors studied 709 persons with PD, which show that the non-coding GBA1 rs3115534 risk variant is associated with increased RBD symptomatology in Nigerians with PD. Further research is required to assess association with polysomnography-defined RBD.
State-dependent GABAergic regulation of striatal spiny projection neuron excitability
By Devin Della Maggiora onOur results demonstrate that GABAARs can work in concert with iGluRs to excite adult SPNs when they are in the resting down-state, suggesting that their inhibitory role is limited to brief periods near spike threshold. This state-dependence calls for a reformulation of the role intrastriatal GABAergic circuits.