scholarly journals Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5/mortalin in Drosophila

2020 ◽  
Author(s):  
Jun-yi Zhu ◽  
Shabab B. Hannan ◽  
Nina M. Dräger ◽  
Natalia Vereshchagina ◽  
Ann-Christin Krahl ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Active Zone ◽  
Neuromuscular Junctions ◽  
Early Stage ◽  
Atp Depletion ◽  
Synapse Maturation ◽  
Adult Model ◽  
Cytoskeleton Rearrangements ◽  
Autophagy Inhibition ◽  
Functional Defects

AbstractWe investigate in larval and adult Drosophila models whether loss of the mitochondrial chaperone Hsc70-5/mortalin is sufficient to cause pathological alterations commonly observed in Parkinson disease. At affected larval neuromuscular junctions, no effects on terminal size, bouton size or number, synapse size, or number were observed, suggesting that we study an early stage of pathogenesis. At this stage, we noted a loss of synaptic vesicle proteins and active zone components, delayed synapse maturation, reduced evoked and spontaneous excitatory junctional potentials, increased synaptic fatigue, and cytoskeleton rearrangements. The adult model displays ATP depletion, altered body posture, and susceptibility to heat-induced paralysis. Adult phenotypes could be suppressed by knockdown of DJ-1b, LRRK, p50, p150, Atg1, Atg101, Atg5, Atg7, and Atg12. The knockdown of components of the autophagy machinery or overexpression of human mortalin broadly rescued larval and adult phenotypes, while disease-associated HSPA9 variants did not. Overexpression of Pink1 or promotion of autophagy exacerbated defects.

Patterns of striatal dopamine depletion in early Parkinson disease

Neurology ◽  
2020 ◽  
Vol 95 (3) ◽  
pp. e280-e290 ◽  
Author(s):  
Seok Jong Chung ◽  
Hye Sun Lee ◽  
Han Soo Yoo ◽  
Yang Hyun Lee ◽  
Phil Hyu Lee ◽  
...  
Keyword(s):  
Factor Analysis ◽  
Parkinson Disease ◽  
Cox Regression ◽  
Early Stage ◽  
Freezing Of Gait ◽  
Striatal Dopamine ◽  
Dopamine Depletion ◽  
Wearing Off ◽  
Striatal Dopamine Depletion ◽  
Selective Dopamine

ObjectiveTo investigate whether the patterns of striatal dopamine depletion on dopamine transporter (DAT) scans could provide information on the long-term prognosis in Parkinson disease (PD).MethodsWe enrolled 205 drug-naive patients with early-stage PD, who underwent 18F-FP-CIT PET scans at initial assessment and received PD medications for 3 or more years. After quantifying the DAT availability in each striatal subregion, factor analysis was conducted to simplify the identification of striatal dopamine depletion patterns and to yield 4 striatal subregion factors. We assessed the effect of these factors on the development of levodopa-induced dyskinesia (LID), wearing-off, freezing of gait (FOG), and dementia during the follow-up period (6.84 ± 1.80 years).ResultsThe 4 factors indicated which striatal subregions were relatively preserved: factor 1 (caudate), factor 2 (more-affected sensorimotor striatum), factor 3 (less-affected sensorimotor striatum), and factor 4 (anterior putamen). Cox regression analyses using the composite scores of these striatal subregion factors as covariates demonstrated that selective dopamine depletion in the sensorimotor striatum was associated with a higher risk for developing LID. Selective dopamine loss in the putamen, particularly in the anterior putamen, was associated with early development of wearing-off. Selective involvement of the anterior putamen was associated with a higher risk for dementia conversion. However, the patterns of striatal dopamine depletion did not affect the risk of FOG.ConclusionsThese findings suggested that the patterns of striatal dopaminergic denervation, which were estimated by the equation derived from the factor analysis, have a prognostic implication in patients with early-stage PD.

Plasma Metabolome Signature in Patients with Early-stage Parkinson Disease

2018 ◽  
Vol 6 (1) ◽  
Author(s):  
Elena E. Balashova ◽  
Petr G. Lokhov ◽  
Dmitry L. Maslov ◽  
Oxana P. Trifonova ◽  
Diana M. Khasanova ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Early Stage ◽  
Plasma Metabolome

scholarly journals Effect of early-stage autophagy inhibition in BRAFV600E autophagy-dependent brain tumor cells

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Shadi Zahedi ◽  
Brent E. Fitzwalter ◽  
Andrew Morin ◽  
Sydney Grob ◽  
Michele Desmarais ◽  
...  
Keyword(s):  
Cell Survival ◽  
Tumor Cells ◽  
Late Stage ◽  
Early Stage ◽  
Specific Effect ◽  
Cns Tumors ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Tumor Cell Death ◽  
Autophagy Inhibition

Abstract Autophagy is a multistage process. Progress within the field has led to the development of agents targeting both early (initiation) and late (fusion) stages of this process. The specific stage of autophagy targeted may influence cancer treatment outcomes. We have previously shown that central nervous system (CNS) tumors with the BRAFV600E mutation are autophagy dependent, and late-stage autophagy inhibition improves the response to targeted BRAF inhibitors (BRAFi) in sensitive and resistant cells. Drugs directed toward initiation of autophagy have been shown to reduce tumor cell death in some cancers, but have not been assessed in CNS tumors. We investigated early-stage inhibition for autophagy-dependent CNS tumors. BRAFi-sensitive and resistant AM38 and MAF794 cell lines were evaluated for the response to pharmacologic and genetic inhibition of ULK1 and VPS34, two crucial subunits of the autophagy initiation complexes. Changes in autophagy were monitored by western blot and flow cytometry. Survival was evaluated in short- and long-term growth assays. Tumor cells exhibited a reduced autophagic flux with pharmacologic and genetic inhibition of ULK1 or VPS34. Pharmacologic inhibition reduced cell survival in a dose-dependent manner for both targets. Genetic inhibition reduced cell survival and confirmed that it was an autophagy-specific effect. Pharmacologic and genetic inhibition were also synergistic with BRAFi, irrespective of RAFi sensitivity. Inhibition of ULK1 and VPS34 are potentially viable clinical targets in autophagy-dependent CNS tumors. Further evaluation is needed to determine if early-stage autophagy inhibition is equal to late-stage inhibition to determine the optimal clinical target for patients.

Release and Recycling of the Readily Releasable Vesicle Population in a Synapse Possessing No Reserve Population

2007 ◽  
Vol 97 (6) ◽  
pp. 4048-4057 ◽  
Author(s):  
J. H. Koenig ◽  
Kazuo Ikeda
Keyword(s):  
High Frequency ◽  
Active Zone ◽  
Neuromuscular Junctions ◽  
Recycling Rate ◽  
Spontaneous Release ◽  
Electron Microscopic ◽  
Single Action ◽  
Active Zones ◽  
Evoked Activity ◽  
Microscopic Techniques

We previously demonstrated that the tergotrochanteral muscle (TTM) of Drosophila is innervated by unique synapses that possess a small readily releasable/recycling vesicle population (active zone population), but not the larger reserve vesicle population observed at other neuromuscular junctions in this animal. Using light and electron microscopic techniques and intracellular recording from the G1 muscle fiber of the TTM, the release and recycling characteristics of the readily releasable/recycling population were observed without any possible contribution from a reserve population. Our results indicate 1) the total number of vesicles in synapses presynaptic to the G1 fiber correlates with the total number of quanta that can be released onto this fiber; 2) the number of quanta released by a single action potential onto the G1 fiber is about one half the number of morphologically “docked” vesicles in active zones onto the G1, and this ratio decreases in a partially depleted state; 3) the recycling rate at 1-Hz stimulation, a frequency that does not cause any depression, is 0.24 recycled vesicle/active zone/s; and 4) normal-appearing spontaneous release occurs from the active zone vesicle population and, unlike synapses that possess a reserve population, the frequency of this release is reduced after high-frequency evoked activity.

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