dnc-1/dynactin 1 Knockdown Disrupts Transport of Autophagosomes and Induces Motor Neuron Degeneration

Ikenaka, Kazuhiro; Kawai, Kenichiro; Katsuno, Masahisa; Huang, Zhe; JIANG, Y.; Iguchi, Yohei; Kobayashi, Kyogo; Kimata, Tsubasa; Waza, Masahiro; Tanaka, Fumiaki; Mori, Ikue; Sobue, Gen

doi:10.1371/journal.pone.0054511

Cited by 92 publications

(80 citation statements)

References 54 publications

(63 reference statements)

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“…In agreement with this model impaired trafficking of autophagosomes6434445 or defective BDNF/TrkB signalling are associated with neurodegeneration1920.…”

Section: Resultssupporting

confidence: 63%

Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration

et al. 2017

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Autophagosomes primarily mediate turnover of cytoplasmic proteins or organelles to provide nutrients and eliminate damaged proteins. In neurons, autophagosomes form in distal axons and are trafficked retrogradely to fuse with lysosomes in the soma. Although defective neuronal autophagy is associated with neurodegeneration, the function of neuronal autophagosomes remains incompletely understood. We show that in neurons, autophagosomes promote neuronal complexity and prevent neurodegeneration in vivo via retrograde transport of brain-derived neurotrophic factor (BDNF)-activated TrkB receptors. p150Glued/dynactin-dependent transport of TrkB-containing autophagosomes requires their association with the endocytic adaptor AP-2, an essential protein complex previously thought to function exclusively in clathrin-mediated endocytosis. These data highlight a novel non-canonical function of AP-2 in retrograde transport of BDNF/TrkB-containing autophagosomes in neurons and reveal a causative link between autophagy and BDNF/TrkB signalling.

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“…In agreement with this model impaired trafficking of autophagosomes6434445 or defective BDNF/TrkB signalling are associated with neurodegeneration1920.…”

Section: Resultssupporting

confidence: 63%

Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration

et al. 2017

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“…This transport is driven by the retrograde motor dynein (Katsumata et al, 2010;Lee et al, 2011;Maday et al, 2012) and its activator dynactin (Ikenaka et al, 2013) (see poster). Not surprisingly, dynein mutations in both fly and mouse models lead to impaired autophagic clearance of polyQ-htt (Ravikumar et al, 2005).…”

Section: Regulation Of Autophagosome Axonal Transport In Diseasementioning

confidence: 99%

“…Autophagosome transport along the axon is primarily retrograde and driven by dynein-dynactin (Ikenaka et al, 2013;Katsumata et al, 2010;Lee et al, 2011;Maday et al, 2012). Autophagosome transport is regulated by huntingtin (Wong and Holzbaur, 2014a), a scaffolding protein that binds dynein directly (Caviston et al, 2007) and also interacts with dynactin (p150 Glued subunit) and kinesin through Huntingtin-associated protein 1 (HAP-1) (Engelender et al, 1997;Li et al, 1995;Li et al, 1998;McGuire et al, 2006;Twelvetrees et al, 2010).…”

Section: Box 2 Regulation Of the Axonal Transport Of Autophagosomesmentioning

confidence: 99%

Autophagosome dynamics in neurodegeneration at a glance

Wong

Holzbaur

2015

Journal of Cell Science

115

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Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway, which is particularly crucial in neurons. There is increasing evidence implicating defective autophagy in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease. Recent work using live-cell imaging has identified autophagy as a predominantly polarized process in neuronal axons; autophagosomes preferentially form at the axon tip and undergo retrograde transport back towards the cell body. Autophagosomes engulf cargo including damaged mitochondria (mitophagy) and protein aggregates, and subsequently fuse with lysosomes during axonal transport to effectively degrade their internalized cargo. In this Cell Science at a Glance article and the accompanying poster, we review recent progress on the dynamics of the autophagy pathway in neurons and highlight the defects observed at each step of this pathway during neurodegeneration.

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“…Perturbations in this complex result in motor neuron degeneration (Ikenaka et al, 2013). Mutations in the dynactin subunit p150 Glued have been linked to familial motor neuron disease (Levy et al, 2006).…”

Section: Mitophagy As a Pathway To Clear Damaged Mitochondriamentioning

confidence: 99%

Exploring new pathways of neurodegeneration in ALS: The role of mitochondria quality control

Palomo

Manfredi

2015

Brain Research

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Neuronal cells are highly dependent on mitochondria, and mitochondrial dysfunction is associated with neurodegenerative diseases. As perturbed mitochondrial function renders neurons extremely sensitive to a wide variety of insults, such as oxidative stress and bioenergetic defects, mitochondrial defects can profoundly affect neuronal fate. Several studies have linked ALS with mitochondrial dysfunction, stemming from observations of mitochondrial abnormalities, both in patients and in cellular and mouse models of familial forms of ALS. Mitochondrial changes have been thoroughly investigated in mutants of superoxide dismutase 1 (SOD1), one of the most common causes of familial ALS, for which excellent cellular and animal models are available, but recently evidence is emerging also in other forms of ALS, both familial and sporadic. Mitochondrial defects in ALS involve many critical physiopathological processes, from defective bioenergetics to abnormal calcium homeostasis, to altered morphology and impaired trafficking. In this review, we summarize established evidence of mitochondrial dysfunction in ALS, especially in SOD1 mutant models of familial ALS. The main focus of the review is on defective mitochondrial quality control (MQC) in ALS. MQC operates at multiple levels to clear damaged proteins through proteostasis and to eliminate irreparably damaged organelles through mitophagy. However, since ALS motor neurons progressively accumulate damaged mitochondria, it is plausible that the MQC is ineffective or overwhelmed by excessive workload imposed by the chronic and extensive mitochondrial damage.

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dnc-1/dynactin 1 Knockdown Disrupts Transport of Autophagosomes and Induces Motor Neuron Degeneration

Cited by 92 publications

References 54 publications

Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration

Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration

Autophagosome dynamics in neurodegeneration at a glance

Exploring new pathways of neurodegeneration in ALS: The role of mitochondria quality control

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