Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons

Zala, Diana; Colin, Emilie; Rangone, Hélène; Liot, Géraldine; Humbert, Sandrine; Saudou, Frédéric

doi:10.1093/hmg/ddn281

Cited by 136 publications

(132 citation statements)

References 33 publications

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“…Corroborating our study, p-(Ser473)Akt/Akt levels were significant decreased in STHdh Q111/Q111 cells [76], in HEK293 cells expressing mHtt with 68 CAG repeats [77] and in HD patient's lymphoblasts and lymphocytes [75]. Akt activation is an early pro-survival striatal response in knock-in Hdh Q111 mice and STHdh Q111/Q111 cells [28]; importantly, activation of IGF-1/Akt pathway caused Htt phosphorylation at Ser421, decreasing mHtt nuclear inclusions and mHtt toxicity [27] and regulated anterograde and retrograde transport defects in HD cortical neurons [78]. Another study demonstrated that p-(Ser473)Akt was unchanged in YAC128 and in R6/2 HD mice, but the levels of p-(Ser421)Htt were decreased in the striatum of YAC128 mice and in cells expressing mHtt [79].…”

Section: Discussionmentioning

confidence: 99%

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Ribeiro

Rosenstock

Oliveira

et al. 2014

Free Radical Biology and Medicine

115

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Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington's disease knock-in striatal cells, Free Radical Biology and Medicine, http://dx.doi.org/10.1016/j. freeradbiomed.2014.06.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Discussionmentioning

confidence: 99%

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Ribeiro

Rosenstock

Oliveira

et al. 2014

Free Radical Biology and Medicine

115

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“…Phosphorylation inhibits mutant huntingtin toxicity by restoring its transport function. 11,12 Therefore, the increase in IGF1 after treatment with triheptanoin may exert direct beneficial effects by restoring huntingtin function and/or by blocking huntingtin toxicity in peripheral organs and possibly in the brain. It is not clear how triheptanoin mediates IGF1 levels, especially because triheptanoin did not increase the levels of BCAA -known to regulate IGF1.…”

Section: Discussionmentioning

confidence: 99%

Dietary anaplerotic therapy improves peripheral tissue energy metabolism in patients with Huntington's disease

et al. 2010

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We previously identified a systemic metabolic defect associated with early weight loss in patients with Huntington's disease (HD), suggesting a lack of substrates for the Krebs cycle. Dietary anaplerotic therapy with triheptanoin is used in clinical trials to promote energy production in patients with peripheral and brain Krebs cycle deficit, as its metabolites -C5 ketone bodiescross the blood-brain barrier. We conducted a short-term clinical trial in six HD patients (UHDRS (Unified Huntington Disease Rating Scale)¼33±13, 15-49) to monitor the tolerability of triheptanoin. We also assessed peripheral markers of short-term efficacy that were shown to be altered in the early stages of HD, that is, low serum IGF1 and 31 P-NMR spectroscopy (NMRS) in muscle. At baseline, 31 P-NMRS displayed two patients with end-exercise muscle acidosis despite a low work output. On day 2, the introduction of triheptanoin was well tolerated in all patients, and in particular, there was no evidence of mitochondrial overload from triheptanoin-derived metabolites. After 4 days of triheptanoin-enriched diet, muscle pH regulation was normalized in the two patients with pretreatment metabolic abnormalities. A significant increase in serum IGF1 was also observed in all patients (205±60 ng/ml versus 246±68 ng/ml, P¼0.010). This study provides a rationale for extending our anaplerotic approach with triheptanoin in HD.

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“…Phosphorylation at various serine residues prevents cleavage of mutant huntingtin into more toxic fragments, decreases neural cell death in vitro (5)(6)(7)(8)(9)(10), and/or restores Htt functions that are compromised by the mutation (8,11). The most dramatic effects have been described for huntingtin phosphorylation at serine 13 and serine 16.…”

mentioning

confidence: 99%

Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

Pardo

Maglione

Alpaugh

et al. 2012

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

142

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Huntington disease (HD) is a progressive neurodegenerative monogenic disorder caused by expansion of a polyglutamine stretch in the huntingtin (Htt) protein. Mutant huntingtin triggers neural dysfunction and death, mainly in the corpus striatum and cerebral cortex, resulting in pathognomonic motor symptoms, as well as cognitive and psychiatric decline. Currently, there is no effective treatment for HD. We report that intraventricular infusion of ganglioside GM1 induces phosphorylation of mutant huntingtin at specific serine amino acid residues that attenuate huntingtin toxicity, and restores normal motor function in already symptomatic HD mice. Thus, our studies have identified a potential therapy for HD that targets a posttranslational modification of mutant huntingtin with critical effects on disease pathogenesis.H untington disease (HD) is an inherited neurodegenerative monogenic disorder caused by the expansion of a polyglutamine stretch beyond 36 residues in the amino-terminal domain of huntingtin (Htt), a protein expressed in most tissues and cells. The mutation causes huntingtin to acquire toxic conformation/s and to affect neuronal function and viability. Medium-sized spiny neurons in the corpus striatum are most affected, but neurodegeneration also occurs in the cerebral cortex and, to a minor extent, in other brain areas, resulting in motor and psychiatric symptoms, as well as cognitive decline.The cellular and molecular mechanisms underlying HD pathogenesis are complex. Both loss and gain of function of mutant huntingtin contribute to cause a wide array of neuronal dysfunctions affecting cell signaling, gene transcription, axonal transport, cell and mitochondrial metabolism as well as neurotransmission (1).In recent years, a breakthrough in HD research has been the discovery that posttranslational modifications of mutant Htt are crucial modulators of mutant Htt toxicity (2-4). Phosphorylation at various serine residues prevents cleavage of mutant huntingtin into more toxic fragments, decreases neural cell death in vitro (5-10), and/or restores Htt functions that are compromised by the mutation (8, 11). The most dramatic effects have been described for huntingtin phosphorylation at serine 13 and serine 16. These two amino acid residues are part of the highly conserved amino-terminal "N17" domain of huntingtin, a domain that regulates huntingtin intracellular localization and association to cellular membranes (12, 13), as well as kinetics of mutant huntingtin aggregation (14,15). Phosphomimetic mutations of serine 13 and serine 16 by aspartic or glutamic acid substitution (S13D and S16D or S13E and S16E) decrease the toxicity of mutant huntingtin fragments in vitro (10, 16). In line with these studies, expression of a phosphomimetic (S13D and S16D) mutant form of expanded full-length huntingtin in a BACHD transgenic mouse model was shown to result in a normal phenotype, with no detectable signs of HD pathology by 12 mo (17).These findings suggest that pharmacological interventions that modulate cell sig...

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Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons

Cited by 136 publications

References 33 publications

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

Dietary anaplerotic therapy improves peripheral tissue energy metabolism in patients with Huntington's disease

Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

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