α-synuclein promotes neuronal dysfunction and death by disrupting the binding of ankyrin to ß-spectrinon
Published: 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 stabilityon
Genetic 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 diseaseon
Published: 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.
Mutations 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.
The 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.
Preprint: 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 rodentson
Preprint: 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.
Preprint: 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.
LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibitionon
These observations define a role for LRRK2 in controlling lysosome degradative activity and support a model wherein LRRK2 hyperactivity may increase Parkinson’s disease risk by suppressing lysosome degradative activity.
Erythroid differentiation dependent interaction of VPS13A with XK at the plasma membrane of K562 cellson
Preprint: ER-PM contacts positive for VPS13A were seldomly observed in undifferentiated K562 cells, despite the presence of XK in these cells at concentrations similar to those observed after differentiation. Findings reveal the interaction of VPS13A with XK at ER-PM contacts requires a permissive state which depends upon cell type and/or functional state of the cell.
Inhibition of striatal dopamine release by the L-type calcium channel inhibitor isradipine co-varies with risk factors for Parkinson’son
Preprint: This data show that LTCC function in DA axons, and isradipine effect, are locally governed and suggest they vary in a manner that in turn might impact on, or reflect, the cellular stress that leads to parkinsonian degeneration.
Synaptic location is a determinant of the detrimental effects of α-synuclein pathology to glutamatergic transmission in the basolateral amygdalaon
αSyn expression is restricted in a subset of glutamatergic synapses in BLA and its aggregation decreases cortico-BLA transmission through both gained toxicity and loss of normal function. These results might be relevant to the reduced cortical control of amygdala function that has been associated with psychiatric deficits in PD.
Preprint: Deviations from normal cluster synchronization patterns are closely associated with various malfunctions, such as neurological disorders in the brain. Here, the authors employ an open-loop control strategy, vibrational control, which does not require any state measurements. Additionally, they conduct numerical experiments to demonstrate their theoretical findings.
Localization of PPM1H phosphatase tunes Parkinson’s disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesison
Preprint: The data support a model in which localization drives PPM1H substrate selection and centriolar PPM1H is critical for regulation of Rab GTPase-regulated ciliogenesis. Moreover, Golgi localized PPM1H maintains active Rab GTPases on the Golgi to carry out their non-ciliogenesis-related functions in membrane trafficking.
Links can also be reported in publications allowing readers to further survey the reported data. The authors discuss benefits for the research community of publishing proteomic data containing a shareable web-link.
LRRK2 regulates the activation of the unfolded protein response and antigen presentation in macrophages during inflammationon
Remarkably, the PD-related protein LRRK2 acted with STING upstream of the UPR to regulate the transition from innate to adaptive immunity, thereby identifying this PD-related protein as a key player in the immune response during inflammation.
Given the clear heterogeneity of DA gut neurons, further investigation is warranted to define their functional signatures and discover their inherent biological differences that put these cells at risk for neurodegeneration.
Global proteomics of neurogenesis in the absence of FBXO7 reveals no obvious alterations in mitochondria or other organelles. These results argue against a general role for FBXO7 in Parkin-dependent mitophagy and point to the need for additional studies to define how FBXO7 mutations promote parkinsonian–pyramidal syndrome.
The molecular inventory of ER proteome remodeling and versatile genetic toolkit provides a quantitative framework for understanding contributions of individual ER-phagy receptors for reshaping ER during cell state transitions.
The authors’ method takes advantage of nanopore long reads and enables unbiased reconstruction of full-length eccDNA sequences. FLED is implemented using Python3 which is freely available on GitHub (https://github.com/FuyuLi/FLED).