BimEL as a possible molecular link between proteasome dysfunction and cell death induced by mutant huntingtin

Leon, Rebecca; Bhagavatula, Nithya; Ulukpo, Onome; McCollum, Mark H.; Wei, Jianning

doi:10.1111/j.1460-9568.2010.07215.x

Cited by 22 publications

(17 citation statements)

References 49 publications

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“…21, 40 These data found further confirmation in two other HD mouse models showing increased striatal BimEL in R6/1 mice at the late stages of disease and in the conditional model Tet/HD94. 22 Collectively, these results demonstrate that mutated htt causes BimEL accumulation and translocation to mitochondria.…”

Section: Bcl-2 Interacting Mediator Of Cell Deathmentioning

confidence: 54%

“…In particular, mutated htt expression induces BimEL accumulation in HEK293T cells, in Neuro-2a cells, 40 in sympathetic superior cervical ganglion neurons 41 and in immortalized striatal cells. 42 BimEL silencing in Neuro-2a cells significantly reduces cell death elicited by mutated htt.…”

Section: Bcl-2 Interacting Mediator Of Cell Deathmentioning

confidence: 99%

“…Mutated htt transfection in PC12 cells increased Bax protein levels fourfold as compared with wt htt transfection; 67 in Neuro2A cells, mutated htt expression induced Bax translocation from the cytosol to the mitochondria. 40 Only one in vitro study argues against a Bax role in mutated htt-induced cell death: King et al 21 showed that in sympathetic superior cervical ganglion (SCG) neurons mutated htt induced Bax-independent cell death.…”

Section: The Pore-forming Proteins Bax and Bcl-2 Antagonist/killer (Bak)mentioning

confidence: 99%

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Defining the role of the Bcl-2 family proteins in Huntington’s disease

et al. 2013

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B-cell lymphoma 2 (Bcl-2) family proteins regulate survival, mitochondria morphology dynamics and metabolism in many cell types including neurons. Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat tract in the IT15 gene that encodes for the protein huntingtin (htt). In vitro and in vivo models of HD and HD patients' tissues show abnormal mitochondrial function and increased cell death rates associated with alterations in Bcl-2 family protein expression and localization. This review aims to draw together the information related to Bcl-2 family protein alterations in HD to decipher their potential role in mutated htt-related cell death and mitochondrial dysfunction.

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Section: Bcl-2 Interacting Mediator Of Cell Deathmentioning

confidence: 54%

Section: Bcl-2 Interacting Mediator Of Cell Deathmentioning

confidence: 99%

Section: The Pore-forming Proteins Bax and Bcl-2 Antagonist/killer (Bak)mentioning

confidence: 99%

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Defining the role of the Bcl-2 family proteins in Huntington’s disease

et al. 2013

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“…It thus seems possible that induction of these and potentially other apoptotic proteins will also require caspase-2 activation. Furthermore, JNK/c-Jun signaling and Bim induction have been implicated in a variety of cell death paradigms in addition to those examined here [54, 55], raising the possibility of caspase-2 involvement in a wide range of apoptotic conditions.…”

Section: Discussionmentioning

confidence: 88%

Caspase-2 is essential for c-Jun transcriptional activation and Bim induction in neuron death

Jean

Ribé

Pero

et al. 2013

Biochemical Journal

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SYNOPSIS Neuronal apoptotic death generally requires de novo transcription, and activation of the transcription factor c-Jun has been shown to be necessary in multiple neuronal death paradigms. Caspase-2 has been implicated in death of neuronal and non-neuronal cells, but its relationship to transcriptional activation has not been clearly elucidated. Here, using two different neuronal apoptotic paradigms, β-amyloid treatment and NGF withdrawal, we examined the hierarchical role of caspase-2 activation in the transcriptional control of neuron death. Both paradigms induce rapid activation of caspase-2 as well as activation of the transcription factor c-Jun and subsequent induction of the pro-apoptotic BH-3 only protein Bim. Caspase-2 activation is dependent on the adaptor protein RAIDD, and both caspase-2 and RAIDD are required for c-Jun activation and Bim induction. Our work, thus, shows that rapid caspase-2 activation is essential for c-Jun activation and Bim induction in neurons subjected to apoptotic stimuli. This places caspase-2 at an apical position in the apoptotic cascade and demonstrates for the first time that caspase-2 can regulate transcription.

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“…The N-terminal coding region (amino acids 1–68) of wild type human htt with 25 polyQ repeats (htt25Q, Addgene plasmid 1187) or 103 polyQ repeats (htt103Q, Addgene plasmid 1186) was attached to an enhanced green fluorescent protein (EGFP) and subcloned into a pcDNA3.1/HisB vector [19]. Human HIP14 cDNA in a pCMV6-Entry vector was purchased from Origene.…”

Section: Methodsmentioning

confidence: 99%

Palmitoylation and trafficking of GAD65 are impaired in a cellular model of Huntington's disease

Rush

Leon

McCollum

et al. 2012

Biochemical Journal

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Synopsis Huntington disease (HD) is caused by an expanded polyglutamine repeat in the huntingtin protein. GABAergic medium spiny neurons in the striatum are mostly affected in HD. However, mutant huntingtin (mhtt)-induced molecular changes in these neurons remain largely unknown. This study focuses on the effect of mhtt on the subcellular localization of glutamic acid decarboxylase (GAD), the enzyme responsible for synthesizing GABA. In this study, we report that the subcellular distribution of GAD is significantly altered in two neuronal cell lines that express either the N-terminus or full length mhtt. GAD65 is predominantly associated with Golgi membrane in cells expressing normal htt. However, it diffuses in the cytosol of cells expressing mhtt. As a result, vesicle-associated GAD65 trafficking is impaired. Since palmitoylation of GAD65 is required for GAD65 trafficking, we then demonstrate that palmitoylation of GAD65 is reduced in the HD model. Furthermore, overexpression of huntingtin-interacting protein 14, the enzyme responsible for palmitoylating GAD65 in vivo, could rescue GAD65 palmitoylation and vesicle-associated GAD65 trafficking. Taken together, our data support the idea that GAD65 palmitoylation is important for the delivery of GAD65 to inhibitory synapses and suggest that impairment of GAD65 palmitoylation by mhtt may lead to altered inhibitory neurotransmission in HD.

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BimEL as a possible molecular link between proteasome dysfunction and cell death induced by mutant huntingtin

Cited by 22 publications

References 49 publications

Defining the role of the Bcl-2 family proteins in Huntington’s disease

Defining the role of the Bcl-2 family proteins in Huntington’s disease

Caspase-2 is essential for c-Jun transcriptional activation and Bim induction in neuron death

Palmitoylation and trafficking of GAD65 are impaired in a cellular model of Huntington's disease

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