Together 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.
This 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
Symptom 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).
In 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 miceon
Taken 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.
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.
Post-fibrillization nitration of alpha-synuclein abolishes its seeding activity and pathology formation in primary neurons and in vivoon
The 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.
Little 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.
Clinically 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.
α-Synuclein promotes neuronal dysfunction and death by disrupting the binding of ankyrin to β-spectrinon
These findings outline a previously undescribed mechanism of α-synuclein neurotoxicity and thus suggest potential new therapeutic approaches in Parkinson's disease and related disorders.
LRRK2 suppresses lysosome degradative activity in macrophages and microglia via transcription factor E3 inhibitionon
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.
Membrane potential phase shifts differ for excitation vs. inhibition in resonant pyramidal neurons: a computer modeling studyon
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.
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 miceon
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.
Protein aggregation and calcium dysregulation are hallmarks of familial Parkinson’s disease in midbrain dopaminergic neuronson
Our 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 TMEM55Bon
Our 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.
The authors’ data show that the endo-/lysosomal lipid flippase ATP10B contributes to cellular PC uptake under specific cell stress conditions.
The 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.
The 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.
The 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 studyon
The 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.