Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer’s disease neurons

Tammineni, Prasad; Ye, Xuan; Feng, Tuancheng; Aikal, Daniyal; Cai, Qian

doi:10.7554/elife.21776

Cited by 132 publications

(115 citation statements)

References 81 publications

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“…Misfolded proteins generated in axons and dendrites are retrogradely transported to the lysosome-rich microtubule-organizing center (MTOC). In MTOC, they are packed into aggresomes, and subsequently degraded in the lysosome [47,48]. These functions are regulated by histone deacetylase-6 (HDAC6).…”

Section: Role Of Hdac6 In Aggrephagymentioning

confidence: 99%

“…This complex is necessary for the fast axonal transport of aggregates and autophagy vacuoles to the perinuclear space for lysosomal degradation [86]. Impairment in their axonal transportation affects their lysosomal degradation [47]. Moreover, this impairment increases the aggregates level in neuronal axons and synapses.…”

Section: Dysregulation In Aggregates Retrograde Transport In Admentioning

confidence: 99%

“…This fusion results in membrane expansion, neuronal dystrophy, and neurodegeneration. Autophagy vacuole accumulation in distal end of neurons imposes neuronal autophagy stress in AD [47]. These synaptic autophagy vacuoles and aggregates clearance failure imposes synaptic toxicity resulting in impaired synaptic plasticity and memory dysfunction ( Figure 2) [90,91].…”

Section: Dysregulation In Aggregates Retrograde Transport In Admentioning

confidence: 99%

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Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

Malampati

Song

Tong

et al. 2020

Cells

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Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases in older individuals with specific neuropsychiatric symptoms. It is a proteinopathy, pathologically characterized by the presence of misfolded protein (Aβ and Tau) aggregates in the brain, causing progressive dementia. Increasing studies have provided evidence that the defect in protein-degrading systems, especially the autophagy-lysosome pathway (ALP), plays an important role in the pathogenesis of AD. Recent studies have demonstrated that AD-associated protein aggregates can be selectively recognized by some receptors and then be degraded by ALP, a process termed aggrephagy. In this study, we reviewed the role of aggrephagy in AD development and discussed the strategy of promoting aggrephagy using small molecules for the treatment of AD.

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Section: Role Of Hdac6 In Aggrephagymentioning

confidence: 99%

Section: Dysregulation In Aggregates Retrograde Transport In Admentioning

confidence: 99%

Section: Dysregulation In Aggregates Retrograde Transport In Admentioning

confidence: 99%

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Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

Malampati

Song

Tong

et al. 2020

Cells

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“…Defects in autophagic flux (Lumkwana et al, 2017;Menzies et al, 2017;Nixon, 2013), AV transport (Tammineni et al, 2017), and lysosomal function (Gowrishankar et al, 2015;Lee et al, 2011aLee et al, , 2011b have been implicated in various neurodegenerative diseases. Furthermore, previous studies have identified mutations in organelle transport machinery that are linked to neurodegenerative disease (Maday et al, 2012;Millecamps and Julien, 2013).…”

Section: Discussionmentioning

confidence: 99%

Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons

Stavoe

Holzbaur

2018

Preprint

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SUMMARYAutophagy defects have been implicated in multiple late-onset neurodegenerative diseases. Since aging is the most common risk factor in neurodegeneration, we asked how autophagy is modulated in aging neurons. We compared the dynamics of autophagosome biogenesis in neurons from young adult and aged mice, identifying a significant decrease in biogenesis during aging. Autophagosome assembly kinetics are disrupted, with frequent production of stalled isolation membranes in neurons from aged mice; these precursors failed to resolve into LC3-positive autophagosomes. We did not detect alterations in the initial induction/nucleation steps of autophagosome formation. However, we found that the transmembrane protein Atg9 remained aberrantly associated with stalled isolation membranes, suggesting a specific disruption in the WIPI-dependent retrieval of Atg9. Depletion of WIPI2 from young neurons was sufficient to induce a similar deficit. Further, exogenous expression of WIPI2 in neurons from aged mice was sufficient to restore autophagosome biogenesis to the rates seen in neurons from young adult mice, suggesting a novel therapeutic target for age-associated neurodegeneration.

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“…Given their distance from the cell soma and high metabolic demand, synapses poise a significant challenge to neurons, as they have to maintain and ensure a stable functional pool of proteins (Tammineni et al, 2017). How might this be achieved?…”

Section: Introductionmentioning

confidence: 99%

Light-Activated ROS Production Induces Synaptic Autophagy

et al. 2019

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The regulated turnover of synaptic vesicle (SV) proteins is thought to involve the ubiquitin-dependent tagging and degradation through endo-lysosomal and autophagy pathways. Yet, it remains unclear which of these pathways are used, when they become activated, and whether SVs are cleared en masse together with SV proteins or whether both are degraded selectively. Equally puzzling is how quickly these systems can be activated and whether they function in real-time to support synaptic health. To address these questions, we have developed an imaging-based system that simultaneously tags presynaptic proteins while monitoring autophagy. Moreover, by tagging SV proteins with a light-activated ROS generator, Supernova, it was possible to temporally control the damage to specific SV proteins and assess their consequence to autophagy-mediated clearance mechanisms and synaptic function. Our results show that, in mouse hippocampal neurons of either sex, presynaptic autophagy can be induced in as little as 5-10 min and eliminates primarily the damaged protein rather than the SV en masse. Importantly, we also find that autophagy is essential for synaptic function, as light-activated damage to, for example, Synaptophysin only compromises synaptic function when autophagy is simultaneously blocked. These data support the concept that presynaptic boutons have a robust highly regulated clearance system to maintain not only synapse integrity, but also synaptic function.

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Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer’s disease neurons

Cited by 132 publications

References 81 publications

Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons

Light-Activated ROS Production Induces Synaptic Autophagy

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