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.
Membrane potential phase shifts differ for excitation vs. inhibition in resonant pyramidal neurons: a computer modeling study
By savannah onThe 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.
The lipid flippase ATP10B enables cellular lipid uptake under stress conditions
By savannah onPublished: The authors' data shows that the endo-/lysosomal lipid flippase ATP10B contributes to cellular PC uptake under specific cell stress conditions. View original preprint.
ATG9 vesicles comprise the seed membrane of mammalian autophagosomes
By savannah onThe ratios of ATG9 and LC3-II at different stages of maturation demonstrate that ATG9 proteins are not continuously integrated, but rather are present on the seed vesicles only and become diluted in the expanding autophagosome membrane.
Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex
By savannah onThe presence of PI3KC3-C1 induces a rearrangement of ULK1C from a FIP200:ATG13:ULK1 2:1:1 to a 2:2:2 stoichiometry by dislocating an ATG13 loop from an inhibitory site on the dimeric FIP200 scaffold. This suggests a mechanism for the initiation of autophagy through PI3KC3-C1-induced dimerization of ULK1 as bound to FIP200, followed by an activating trans-autophosphorylation of ULK1.
Basal ganglia neurons in healthy and Parkinsonian primates generate recurring sequences of spikes
By savannah onThe authors conclude that basal ganglia neurons fire in recognizable sequences of ISIs, whose incidence is influenced by the induction of parkinsonism.
Impact of the dopamine system on long-term cognitive impairment in Parkinson’s disease: An exploratory study
By savannah onThe study provides preliminary evidence that alterations in the dopamine system predict the development of clinically-relevant, cognitive impairment in Parkinson’s disease. If replicated and determined to be causative, they demonstrate that the dopamine system is instrumental to cognitive health status throughout the disease course.
Urinary bis(monacylglycerol) phosphate (BMP) levels are higher in LRRK2 and GBA1 variant carriers but do not predict disease progression in PPMI cohorts
By savannah onThese data support the utility of BMP as a target modulation biomarker in therapeutic trials of genetic and sPD but not as a prognostic or disease progression biomarker.
Updated percentiles for the University of Pennsylvania Smell Identification Test in adults 50 years of age and older
By savannah onThe objective was to develop updated percentiles, based on substantially larger samples than previous norms, to more finely discriminate age- and sex-specific University of Pennsylvania Smell Identification Test (UPSIT) performance among ≥50-year-old adults who may be candidates for studies of prodromal neurodegenerative diseases.