Phosphorylation of Arfaptin 2 at Ser260 by Akt Inhibits PolyQ-huntingtin-induced Toxicity by Rescuing Proteasome Impairment

Rangone, Hélène; Pardo, Raúl; Colin, Emilie; Girault, Jean‐Antoine; Saudou, Frédéric

doi:10.1074/jbc.m407528200

Cited by 44 publications

(33 citation statements)

References 35 publications

(45 reference statements)

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“…The expression of HttQ25 has no effect on proteasome activity, whereas expression of HttQ103 caused a 40% decrease in proteasome activity, in agreement with other studies (Jana et al, 2001;Nishitoh et al, 2002;Rangone et al, 2005). When HttQ103 was transfected in PrP C -depleted cells, there was a further reduction in proteasome activity.…”

Section: Prpsupporting

confidence: 79%

Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation

Lee

Panzera

Rogawski

et al. 2007

Journal of Cell Science

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The effect of normal cellular prion protein (PrPC) on abnormal protein aggregation was examined by transfecting huntingtin fragments (Htt) into SN56 neuronal-derived cells depleted of PrPC by RNA interference. PrPC depletion caused an increase in both the number of cells containing granules and the number of apoptotic cells. Consistent with the increase in Htt aggregation, PrPC depletion caused an decrease in proteasome activity and a decrease in the activities of cellular defense enzymes compared with control cells whereas reactive oxygen species (ROS) increased more than threefold. Therefore, PrPC may protect against Htt toxicity in neuronal cells by increasing cellular defense proteins, decreasing ROS and increasing proteasome activity thereby increasing Htt degradation. Depletion of endogenous PrPC in non-neuronal Caco-2 and HT-29 cells did not affect ROS levels or proteasome activity suggesting that only in neuronal cells does PrPC confer protection against Htt toxicity. The protective effect of PrPC was further evident in that overexpression of mouse PrPC in SN56 cells transfected with Htt caused a decrease in both the number of cells with Htt granules and the number of apoptotic cells, whereas there was no effect of PrPC expression in non-neuronal NIH3T3 or CHO cells. Finally, in chronically scrapie (PrPSc)-infected cells, ROS increased more than twofold while proteasome activity was decreased compared to control cells. Although this could be a direct effect of PrPSc, it is also possible that, since PrPC specifically prevents pathological protein aggregation in neuronal cells, partial loss of PrPC itself increases PrPSc aggregation.

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Section: Prpsupporting

confidence: 79%

Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation

Lee

Panzera

Rogawski

et al. 2007

Journal of Cell Science

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“…showed that exogenously expressed arfaptin-1 and arfaptin-2 are found in perinuclear region (5,17,18). As exogenously expressed arfaptin-1 in the perinuclear region was redistributed into the cytoplasm upon treating cells with BFA (5 g/ml, 10 min), Kanoh et al (5) suggested that it was localized to the Golgi apparatus.…”

Section: Localization Of Arfaptins To the Trans-golgi-early Studiesmentioning

confidence: 99%

“…On the other hand, arfaptin-2/POR1 interacts with all Arf proteins examined (14,15) and an Arf-like protein, Arl1 (15,16), regulates cytoskeletal rearrangements at the cell periphery induced by Arf6 and Rac1 (6), and modifies aggregation of polyglutamine-expanded huntingtin (17,18). Thus, arfaptins appear to function at diverse cellular locations.…”

mentioning

confidence: 99%

Arfaptins Are Localized to the trans-Golgi by Interaction with Arl1, but Not Arfs

Man

Kondo

Koga

et al. 2011

Journal of Biological Chemistry

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“…Overexpression of constitutively active Akt is sufficient to rescue pathologic phenotypes, such as the formation of nuclear inclusions, in primary rat brain cultures expressing mHtt (33). Akt also regulates inclusions indirectly by phosphorylating other proteins such as the ADP ribosylation factor-interacting protein arfaptin2, which rescues mHtt-induced proteasomal impairment (34). mHtt is phosphorylated by Akt at the S421 site, which restores fast axonal transport by altering the mHtt interaction with dynactin (35).…”

Section: Discussionmentioning

confidence: 99%

Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

Ahmed

Sbodio

Harraz

et al. 2015

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

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Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine repeat expansion in mutant huntingtin (mHtt). Despite the known genetic cause of HD, the pathophysiology of this disease remains to be elucidated. Inositol polyphosphate multikinase (IPMK) is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions. We report a severe loss of IPMK in the striatum of HD patients and in several cellular and animal models of the disease. This depletion reflects mHtt-induced impairment of COUP-TF-interacting protein 2 (Ctip2), a striatal-enriched transcription factor for IPMK, as well as alterations in IPMK protein stability. IPMK overexpression reverses the metabolic activity deficit in a cell model of HD. IPMK depletion appears to mediate neural dysfunction, because intrastriatal delivery of IPMK abates the progression of motor abnormalities and rescues striatal pathology in transgenic murine models of HD.Huntington's disease | inositol polyphosphate multikinase | IPMK | Ctip2 | Akt

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Phosphorylation of Arfaptin 2 at Ser260 by Akt Inhibits PolyQ-huntingtin-induced Toxicity by Rescuing Proteasome Impairment

Cited by 44 publications

References 35 publications

Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation

Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation

Arfaptins Are Localized to the trans-Golgi by Interaction with Arl1, but Not Arfs

Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

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