The Regulation of Autophagosome Dynamics by Huntingtin and HAP1 Is Disrupted by Expression of Mutant Huntingtin, Leading to Defective Cargo Degradation

Wong, Yvette C.; Holzbaur, Erika L.F.

doi:10.1523/jneurosci.1870-13.2014

Cited by 329 publications

(344 citation statements)

References 63 publications

(8 reference statements)

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“…A defect in selective autophagic clearance of the ironbinding protein ferritin (ferritinophagy) with loss of HTT function in HD patients and mice may therefore reflect an impairment in ferritinophagy (13,44,45). Both mutant HTT expression and HTT knockdown are found to impair axonal trafficking of vesicles, mitochondria, and autophagosomes in neurons in vitro and in vivo (7)(8)(9)12), consistent with a loss of Atg11/Atg23-like membrane trafficking.…”

Section: Discussionmentioning

confidence: 96%

“…Loss of HTT in mouse cells reduces primary cilia formation, and deletion of HTT in ependymal cells leads to alteration of the cilia layer, suggesting a role for HTT in ciliogenesis (6). Mutant HTT expression and HTT knockdown have also been found to impair axonal trafficking of vesicles, mitochondria, and autophagosomes in neurons in vitro and in vivo (7)(8)(9). A clear molecular mechanism to relate these findings to the function of the HTT protein, however, has not yet emerged.…”

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confidence: 99%

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Potential function for the Huntingtin protein as a scaffold for selective autophagy

Ochaba

Lukácsovich²,

Csikos

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

252

228

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Although dominant gain-of-function triplet repeat expansions in the Huntingtin (HTT) gene are the underlying cause of Huntington disease (HD), understanding the normal functions of nonmutant HTT protein has remained a challenge. We report here findings that suggest that HTT plays a significant role in selective autophagy. Loss of HTT function in Drosophila disrupts starvationinduced autophagy in larvae and conditional knockout of HTT in the mouse CNS causes characteristic cellular hallmarks of disrupted autophagy, including an accumulation of striatal p62/SQSTM1 over time. We observe that specific domains of HTT have structural similarities to yeast Atg proteins that function in selective autophagy, and in particular that the C-terminal domain of HTT shares structural similarity to yeast Atg11, an autophagic scaffold protein. To explore possible functional similarity between HTT and Atg11, we investigated whether the C-terminal domain of HTT interacts with mammalian counterparts of yeast Atg11-interacting proteins. Strikingly, this domain of HTT coimmunoprecipitates with several key Atg11 interactors, including the Atg1/Unc-51-like autophagy activating kinase 1 kinase complex, autophagic receptor proteins, and mammalian Atg8 homologs. Mutation of a phylogenetically conserved WXXL domain in a C-terminal HTT fragment reduces coprecipitation with mammalian Atg8 homolog GABARAPL1, suggesting a direct interaction. Collectively, these data support a possible central role for HTT as an Atg11-like scaffold protein. These findings have relevance to both mechanisms of disease pathogenesis and to therapeutic intervention strategies that reduce levels of both mutant and normal HTT.rodegenerative disorder caused by an expansion of a CAG trinucleotide repeat encoding a polyglutamine (polyQ) tract near the N terminus of the 350-kD Huntingtin protein (HTT) (1). Identifying the normal biological function of the HTT protein is important in the effort to design and implement effective therapeutic interventions for HD, but has proved challenging.In the mouse, loss of HTT leads to lethality during gastrulation at embryonic day 7 (2-4). Conditional inactivation of HTT in the mouse forebrain at postnatal or late embryonic stages causes a progressive neurodegenerative phenotype associated with neuronal degeneration, motor phenotypes, and early mortality (5). Loss of HTT in mouse cells reduces primary cilia formation, and deletion of HTT in ependymal cells leads to alteration of the cilia layer, suggesting a role for HTT in ciliogenesis (6). Mutant HTT expression and HTT knockdown have also been found to impair axonal trafficking of vesicles, mitochondria, and autophagosomes in neurons in vitro and in vivo (7-9). A clear molecular mechanism to relate these findings to the function of the HTT protein, however, has not yet emerged.In contrast to the embryonic lethality observed in the mouse, Drosophila lacking the endogenous Htt gene develop normally. However, adult Drosophila HTT loss-of-function (LOF) flies show an accelerated neurodege...

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Potential function for the Huntingtin protein as a scaffold for selective autophagy

Ochaba

Lukácsovich²,

Csikos

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

252

228

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“…ALS patients also exhibit increased levels of the autophagy initiation proteins beclin-1 and the Atg5-Atg12 complex (Hetz et al, 2009) and an overall increase in autophagosomes (Sasaki, 2011). In Huntington's disease models, autophagosome formation at the axon tip and density along the axon are not altered (Baldo et al, 2013;MartinezVicente et al, 2010;Wong and Holzbaur, 2014a).…”

Section: Autophagosome Biogenesis In Neuronsmentioning

confidence: 99%

“…Using live-cell imaging in cultured neurons, recent studies have found that autophagosomes that undergo axonal transport engulf both mutant SOD1 (Maday et al, 2012) and polyQ-htt (Wong and Holzbaur, 2014a), further demonstrating that autophagy contributes to protein turnover in the axon. Thus, autophagy might play a crucial role in regulating aggregate formation both at synapses and along the axon.…”

Section: Cargo Loading Of Disease-associated Proteinsmentioning

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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“…Dendritic release of secreted proteins (e.g., BDNF, NT-3, and NT-4) and diffusible molecules, such as nitric oxide, can transsynaptically regulate neurotransmitter release [43][44][45] . Injury of motoneuron projections to myocytes caused synaptic remodeling of inputs to motoneurons which was influenced by nitric oxide synthesis 46 .…”

Section: Discussionmentioning

confidence: 99%

Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling

Nagendran

Larsen

Bigler

et al. 2016

Preprint

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Injury of CNS nerve tracts remodels circuitry through dendritic spine loss and hyper-excitability, thus influencing recovery. Due to the complexity of the CNS, a mechanistic understanding of injury-induced synaptic remodeling remains unclear. Using microfluidic chambers to separate and injure distal axons, we show that axotomy causes retrograde dendritic spine loss at directly injured pyramidal neurons followed by retrograde presynaptic hyper-excitability. These remodeling events require activity at the site of injury, axon-to-soma signaling, and transcription. Similarly, directly injured corticospinal neurons in vivo also exhibit a specific increase in spiking following axon injury. Axotomy-induced hyperexcitability of cultured neurons coincides with elimination of inhibitory inputs onto injured neurons, including those formed onto dendritic spines. Netrin-1 downregulation occurs following axon injury and exogenous netrin-1 applied after injury normalizes spine density, presynaptic excitability, and inhibitory inputs at injured neurons. Our findings show that intrinsic signaling within damaged neurons regulates synaptic remodeling and involves netrin-1 signaling.

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The Regulation of Autophagosome Dynamics by Huntingtin and HAP1 Is Disrupted by Expression of Mutant Huntingtin, Leading to Defective Cargo Degradation

Cited by 329 publications

References 63 publications

Potential function for the Huntingtin protein as a scaffold for selective autophagy

Potential function for the Huntingtin protein as a scaffold for selective autophagy

Autophagosome dynamics in neurodegeneration at a glance

Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling

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