Proteostasis and lysosomal quality control deficits in Alzheimer’s disease neurons
By savannah onCompounds enhancing lysosomal function broadly ameliorate AD-associated pathologies. The authors’ findings establish cell-autonomous LQC dysfunction in neurons as a central vulnerability in aging and AD pathogenesis.
Autophagy preferentially degrades non-fibrillar polyQ aggregates
By savannah onPreprint: These results suggest that the limited efficiency of autophagy in clearing polyQ aggregates is due to the inability of autophagosomes to interact productively with the non-deformable, fibrillar disease aggregates.
RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors
By savannah onPreprint: Gain-of-function mutations in the LRRK2 gene cause Parkinson’s disease (PD), characterized by debilitating motor and non-motor symptoms. The authors’ results reveal a mechanism by which pathogenic hyperactive LRRK2 may contribute to the altered synaptic homeostasis associated with characteristic non-motor and cognitive manifestations of PD.
Three-step docking by WIPI2, ATG16L1, and ATG3 delivers LC3 to the phagophore
By savannah onIn a near-complete pathway from the initial membrane recruitment to the LC3 lipidation reaction, the three-step targeting of the ATG12--ATG5-ATG16L1 machinery establishes a high level of regulatory control.
Leucine-rich repeat kinase 2 at a glance
By savannah onThis Cell Science at a Glance article (and the accompanying poster) deliver a snapshot of the authors’ current understanding of LRRK2 function, dysfunction, and links to disease. Journal of Cell Science (2023) 136, jcs259724 (pending publication).
Generation of human-induced pluripotent-stem-cell-derived cortical neurons for high-throughput imaging of neurite morphology and neuron maturation
By savannah onA STAR protocol that describes how to differentiate cryopreserved human cortical neuronal progenitors into mature cortical neurons for high-throughput imaging analysis.
KAT8 compound inhibition inhibits PINK1/Parkin-dependent mitophagy and initiates mitochondrial delivery to lysosomes
By savannah onPreprint: The KAT8 gene encodes a lysine acetyltransferase and represents the catalytically active subunit of the non-specific lethal (NSL) epigenetic remodeling complex. The authors’ study provided additional support for KAT8 inhibition as a regulator of mitophagy and autophagy processes.
A mono- and intralink filter (mi-filter) to reduce false identifications in cross-linking mass spectrometry data
By savannah onThe authors show that this simple and intuitive filter has a dramatic effect on different types of cross-linking data ranging from individual protein complexes over medium-complexity affinity enrichments to proteome-wide cell lysates and significantly reduces the number of false-positive identifications for inter-protein links in all these types of XL-MS data.
Phenotypic effect of GBA1 variants in individuals with and without Parkinson disease: The RAPSODI study
By savannah onPreprint: The authors’ results support previous evidence that GBA1-positive PD has a specific phenotype with more severe non-motor symptoms. However, the authors did not reproduce previous findings of more frequent prodromal PD signs in non-affected GBA1 carriers.
Adeno-associated viral vectors for functional intravenous gene transfer throughout the non-human primate brain
By savannah onCAP-Mac is shown to have potential for non-invasive systemic gene transfer in the brains of non-human primates.
Evaluation of an adapted semi-automated DNA extraction for human salivary shotgun metagenomics
By savannah onPreprint: This study demonstrates that the authors’ semi-automated protocol is suitable for shotgun metagenomic analysis, while allowing for a better sample treatment logistic with reduced technical variability and without compromising the structure of the oral microbiome.
α-synuclein expression in response to bacterial ligands and metabolites in gut enteroendocrine cells
By savannah onPreprint: Elevated intracellular α-synuclein increases the likelihood of aggregation and conversion to toxic forms. Factors derived from bacteria induce α-synuclein accumulation in STC-1 cells. Provided support for a mechanism by which exposure of enteroendocrine cells to specific bacterial factors found in PD gut dysbiosis might facilitate accumulation, transmission of α-synuclein pathology from the gut to the brain.
α-synuclein promotes neuronal dysfunction and death by disrupting the binding of ankyrin to ß-spectrin
By savannah onPreprint: The authors’ findings define a specific molecular mechanism by which elevated levels of α-synuclein in Parkinson’s disease and related α-synucleinopathies leads to neuronal dysfunction and death.
The Parkinson’s disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability
By savannah onGenetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, the authors’ data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.
Interaction of an α-synuclein epitope with HLA-DRB1*15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease
By savannah onPublished: Interaction of α-syn32-46 and HLA-DRB1*15:0 is critical for gut inflammation and CD4+ T cell-mediated loss of enteric neurons in humanized mice, suggesting potential mechanisms of prodromal enteric PD.
RBG motif bridge-like lipid transport proteins: Structure, functions, and open questions
By savannah onMutations in some of these proteins result in neurodegenerative diseases. The authors review the known properties and well-established or putative physiological roles of these proteins, and highlight the many questions that remain open about their functions.
Local diffusion in the extracellular space of the brain
By savannah onThe authors highlight emerging technological advances to respectively interrogate and model diffusion through the ECS, and point out how these may contribute in resolving the remaining enigmas of the ECS.
Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates
By savannah onPreprint: Evidence is provided showing that intracellular aggregation of endogenous alpha-synuclein is triggered by NMel accumulation; therefore any therapeutic approach intended to decrease NMel levels may provide appealing choices for the successful implementation of novel PD therapeutics.
Non-ablative disease-modifying effects of magnetic resonance-guided focused ultrasound in neuromelanin-producing parkinsonian rodents
By savannah onPreprint: The authors' findings indicate that tFUS treatment applied at prodromal/early disease stages provides by itself extended structural and functional preservation of the nigrostriatal pathway in neuromelanin-producing parkinsonian rats without causing overt neuronal damage.
Reduced thalamic excitation to motor cortical pyramidal tract neurons in parkinsonism
By savannah onPreprint: The authors’ data suggest that cell subtype- and synapse-specific adaptations in M1 contribute to altered cortical outputs in parkinsonism and are important aspects of PD pathophysiology.