Localization of PPM1H phosphatase tunes Parkinson’s disease-linked LRRK2 kinase-mediated Rab GTPase phosphorylation and ciliogenesis
By savannah onPreprint: 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.
CURTAIN – A Unique web-based tool for exploration and sharing of MS-based proteomics data
By savannah onPublished: 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. View original preprint.
LRRK2 regulates the activation of the unfolded protein response and antigen presentation in macrophages during inflammation
By savannah onRemarkably, 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.
Characterizing the diversity of enteric neurons using Dopamine Transporter (DAT)-Cre reporter mice
By savannah onGiven 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.
PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems
By savannah onGlobal 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.
Combinatorial selective ER-phagy remodels the ER during neurogenesis
By savannah onThe endoplasmic reticulum (ER) is crucial for various cellular functions. ER proteome is modified by autophagy, especially in neurons. Specific receptors target ER components for degradation, impacting neuronal health. View original preprint.
Detecting Full-Length EccDNA with FLED and long-reads sequencing
By savannah onThe 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).
Synapsin E-domain is essential for α-synuclein function
By savannah onTogether with previous studies implicating the E-domain in clustering SVs, the authors’ experiments advocate a cooperative role for these two proteins in maintaining physiologic SV clusters. View original preprint.
PINK1: From Parkinson’s disease to mitophagy and back again
By savannah onThis perspective discusses the implications of a 2010 PLOS Biology paper that shed light on the functional importance of PINK1 in the mitophagy cascade. https://doi.org/10.1371/journal.pbio.1000298
The longitudinal progression of autonomic dysfunction in Parkinson’s disease: A 7-year study
By savannah onSymptom 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).
Whole proteome copy number dataset in primary mouse cortical neurons
By savannah onIn this article, the authors provide a proteomic reference dataset that has been generated to identify proteins and quantify their level of expression in primary mouse cortical neurons. It represents a summary analysis of previously published data in (Antico et al., 2021).
Synaptotagmin-1-dependent phasic axonal dopamine release is dispensable for basic motor behaviors in mice
By savannah onTaken together, the authors’ findings reveal the striking resilience of DA-dependent motor functions in the context of a near-abolition of phasic DA release, shedding new light on why extensive loss of DA innervation is required to reveal motor dysfunctions in PD.
Spatial transcriptomics reveals molecular dysfunction associated with Lewy pathology
By savannah onPublished: The results identify neurons vulnerable to Lewy pathology in the PD cortex and identify a conserved signature of molecular dysfunction in both mice and humans. View original preprint.
Post-fibrillization nitration of alpha-synuclein abolishes its seeding activity and pathology formation in primary neurons and in vivo
By savannah onThe pattern of PTMs on pathological aggregates, rather than simply their presence, could be a key determinant of their toxicity and neurodegeneration and reconsidering current approaches relying solely on quantifying and correlating the level of pathology to assess the efficacy of novel therapies, as not all α-Syn aggregates in the brain are pathogenic.
Parkinson’s Progression Markers Initiative: A milestone-based strategy to monitor PD progression
By savannah onClinically relevant milestones occur frequently, even in early PD. Milestones were significantly associated with baseline clinical and biological markers, but not with symptomatic treatment. Further studies are necessary to validate these results, further assess the stability of milestones, and explore translating them into an outcome measure suitable for observational and therapeutic studies.
LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition
By savannah onPublished: These discoveries define a mechanism for LRRK2-dependent control of lysosomes and support a model wherein LRRK2 hyperactivity increases Parkinson’s disease risk by suppressing lysosome degradative activity. View original preprint.
Simulations predict differing phase responses to excitation vs. inhibition intheta-resonant pyramidal neurons
By savannah onPublished: The authors hypothesize that intrinsic cellular properties complement network properties and contribute to in vivo phase-shift phenomena such as phase precession, seen in place and grid cells, and phase roll, observed in hippocampal CA1 neurons. View original preprint.
The calcium sensor synaptotagmin-1 is critical for phasic axonal dopamine release in the striatum and mesencephalon, but is dispensable for basic motor behaviors in mice
By savannah onThe authors’ findings reveal the striking resilience of DA-dependent motor functions in the context of a near-abolition of phasic DA release, shedding new light on why extensive loss of DA innervation is required to reveal motor dysfunctions in PD.
Protein aggregation and calcium dysregulation are hallmarks of familial Parkinson’s disease in midbrain dopaminergic neurons
By savannah onOur differentiation paradigm generates an efficient model for studying disease mechanisms in PD and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.
Parkinson’s VPS35[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B
By savannah onPublished: This study uncovers a pathway through which dysfunctional lysosomes resulting from the VPS35 mutation recruit and activate LRRK2 on the lysosomal surface, driving assembly of the RILPL1-TMEM55B complex. View original preprint.
