Autophagy and the endolysosomal system in presynaptic function

Andres-Alonso, Maria; Kreutz, Michael R.; Karpova, Anna

doi:10.1007/s00018-020-03722-5

Cited by 30 publications

(28 citation statements)

References 125 publications

(241 reference statements)

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“…If α-synuclein aggregate is taken up from the presynaptic regions, it is likely to be transported to the cell body by retrograde axonal transport 43 . This idea seems to be consistent with previous reports that extracellular α-synuclein is taken into the cell and transported to the cell body by the endolysosomal pathway, because endolysosomes are also thought to be transported from the synapse to the cell body by retrograde axonal transport 26 , 27 , 46 . In this study, time-course observations of injected mouse brain and primary-cultured cells revealed that the amount of phosphorylated α-synuclein increased concomitantly with retrogradely transport through the axon to the cell body.…”

Section: Discussionsupporting

confidence: 92%

Phosphorylation of endogenous α-synuclein induced by extracellular seeds initiates at the pre-synaptic region and spreads to the cell body

Awa

Suzuki

Masuda-Suzukake

et al. 2022

Sci Rep

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Accumulation of phosphorylated α-synuclein aggregates has been implicated in several diseases, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and is thought to spread in a prion-like manner. Elucidating the mechanisms of prion-like transmission of α-synuclein is important for the development of therapies for these diseases, but little is known about the details. Here, we injected α-synuclein fibrils into the brains of wild-type mice and examined the early phase of the induction of phosphorylated α-synuclein accumulation. We found that phosphorylated α-synuclein appeared within a few days after the intracerebral injection. It was observed initially in presynaptic regions and subsequently extended its localization to axons and cell bodies.　These results suggest that extracellular α-synuclein fibrils are taken up into the presynaptic region and seed-dependently convert the endogenous normal α-synuclein that is abundant there to an abnormal phosphorylated form, which is then transported through the axon to the cell body.

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Section: Discussionsupporting

confidence: 92%

Phosphorylation of endogenous α-synuclein induced by extracellular seeds initiates at the pre-synaptic region and spreads to the cell body

Awa

Suzuki

Masuda-Suzukake

et al. 2022

Sci Rep

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“…Synaptic maintenance needs to cope with the metabolic demand of neurotransmission, as well as with elevated rates of protein turnover and a high membrane exchange that requires efficient delivery and constant supply of newly synthesized proteins (Guedes-Dias and Holzbaur, 2019; Harris et al, 2012). Therefore, removal of damaged proteins and organelles from synaptic sites is essential to sustain synaptic function (Andres-Alonso et al, 2021). Abnormalities in function, trafficking or signaling of mitochondria, lysosomes and endoplasmic reticulum contribute to development of neurodegenerative diseases (Cabral-Miranda and Hetz, 2018;Kerr et al, 2017;Lie and Nixon, 2019;Öztürk et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

A quantitative model of sporadic axonal degeneration in theDrosophilavisual system

Richard

Doubková

Nitta

et al. 2021

Preprint

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In human neurodegenerative diseases, neurons undergo axonal degeneration months to years before they die. Here, we developed a system modelling early degenerative events in Drosophila adult photoreceptor cells. Thanks to the stereotypy of their axonal projections, this system delivers quantitative data on sporadic and progressive axonal degeneration of photoreceptor cells. Using this method, we show that exposure of adult flies to a constant light stimulation for several days overcomes the intrinsic resilience of R7 photoreceptors and leads to progressive axonal degeneration. This was not associated with apoptosis. We furthermore provide evidence that loss of synaptic integrity between R7 and a postsynaptic partner preceded axonal degeneration, thus recapitulating features of human neurodegenerative diseases. Finally, our experiments uncovered that neurotransmission to postsynaptic partners of R7 and their response are required to initiate degeneration, suggesting that postsynaptic cells signal back to the photoreceptor to maintain axonal structure. This model can be used to dissect cellular circuit mechanisms involved in the early events of axonal degeneration, allowing for a better understanding of how neurons cope with stress and lose their resilience capacities.

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“…Autophagy is important for regulating normal cellular processes. [62][63][64] Because lysosomes help degrade intracellular cargo delivered via autophagy and dysfunctional autophagy has been implicated in HIV-1 infection [65][66][67][68] we determined the extent to which HIV-1 Tat affected lysosome degradation of intracellular cargo via autophagy. Consistent with others' findings that Tat disturbs autophagy in microglia and immune cells, 58,69 accumulation of unmetabolized HIV-1 Tat.…”

Section: Hiv-1 Tat-suppressed Autophagic Flux In Astrocytesmentioning

confidence: 99%

HIV‐1 Tat endocytosis and retention in endolysosomes affects HIV‐1 Tat‐induced LTR transactivation in astrocytes

et al. 2022

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The presence of latent HIV‐1 reservoirs in the periphery and brain represents a major obstacle to curing HIV‐1 infection. As an essential protein for HIV‐1 viral replication, HIV‐1 Tat, mostly intracellular, has been implicated in latent HIV‐1 infection. From HIV‐1 infected cells, HIV‐1 Tat is actively secreted and bystander cells uptake the released Tat whereupon it is endocytosed and internalized into endolysosomes. However, to activate the HIV‐1 LTR promoter and increase HIV‐1 replication, HIV‐1 Tat must first escape from the endolysosomes and then enter the nucleus. Here, we tested the hypothesis that HIV‐1 Tat can accumulate in endolysosomes and contribute to the activation of latent HIV‐1 in astrocytes. Using U87MG astrocytoma cells expressing HIV‐1 LTR‐driven luciferase and primary human astrocytes we found that exogenous HIV‐1 Tat enters endolysosomes, resides in endolysosomes for extended periods of time, and induces endolysosome de‐acidification as well as enlargement. The weak base chloroquine promoted the release of HIV‐1 Tat from endolysosomes and induced HIV‐1 LTR transactivation. Similar results were observed by activating endolysosome Toll‐like receptor 3 (TLR3) and TLR7/8. Conversely, pharmacological block of TLRs and knocking down expression levels of TLR3 and TLR7, but not TLR8, prevented endolysosome leakage and attenuated HIV‐1 Tat‐mediated HIV‐1 LTR transactivation. Our findings suggest that HIV‐1 Tat accumulation in endolysosomes may play an important role in controlling HIV‐1 transactivation.

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Autophagy and the endolysosomal system in presynaptic function

Cited by 30 publications

References 125 publications

Phosphorylation of endogenous α-synuclein induced by extracellular seeds initiates at the pre-synaptic region and spreads to the cell body

Phosphorylation of endogenous α-synuclein induced by extracellular seeds initiates at the pre-synaptic region and spreads to the cell body

A quantitative model of sporadic axonal degeneration in theDrosophilavisual system

HIV‐1 Tat endocytosis and retention in endolysosomes affects HIV‐1 Tat‐induced LTR transactivation in astrocytes

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