The Interaction of Aging and Cellular Stress Contributes to Pathogenesis in Mouse and Human Huntington Disease Neurons

Huntington disease (HD) is an ideal model for investigating selective neurodegeneration, as expanded polyQ repeats in the ubiquitously expressed huntingtin (HTT) cause the preferential neurodegeneration in the striatum of the HD patient brains. Here we report that adeno-associated virus (AAV) transduction-mediated depletion of Hap1, the first identified huntingtin-associated protein, in adult HD knock-in (KI) mouse brains leads to selective neuronal loss in the striatum. Further, Hap1 depletion-mediated neuronal loss via AAV transduction requires the presence of mutant HTT. Rhes, a GTPase that is enriched in the striatum and sumoylates mutant HTT to mediate neurotoxicity, binds more N-terminal HTT when Hap1 is deficient. Consistently, more soluble and sumoylated N-terminal HTT is presented in HD KI mouse striatum when HAP1 is absent. Our findings suggest that both Rhes and Hap1 as well as cellular stress contribute to the preferential neurodegeneration in HD, highlighting the involvement of multiple factors in selective neurodegeneration.

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Metabolic State Determines Sensitivity to Cellular Stress in Huntington Disease: Normalization by Activation of PPARγ

PLoS ONE ◽

10.1371/journal.pone.0030406 ◽

2012 ◽

Vol 7 (1) ◽

pp. e30406 ◽

Cited By ~ 21

Author(s):

Youngnam N. Jin ◽

Woong Y. Hwang ◽

Chulman Jo ◽

Gail V. W. Johnson

Keyword(s):

Huntington Disease ◽

Cellular Stress ◽

Metabolic State

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Nucleolar stress controls mutant Huntingtin toxicity and monitors Huntington disease progression

10.1101/2021.07.09.451766 ◽

2021 ◽

Author(s):

Aynur Soenmez ◽

Rasem Mustafa ◽

Salome T Ryll ◽

Francesca Tuorto ◽

Ludivine Wacheul ◽

...

Keyword(s):

Skeletal Muscle ◽

Mouse Model ◽

Huntington Disease ◽

Neurodegenerative Disorder ◽

Cellular Stress ◽

Cellular Stress Response ◽

Cag Repeats ◽

Mutant Huntingtin ◽

The Impact

Transcriptional and cellular stress surveillance deficits are hallmarks of Huntington disease (HD), a fatal autosomal dominant neurodegenerative disorder, caused by a pathological expansion of CAG repeats in the Huntingtin (HTT) gene. The nucleolus, a dynamic nuclear biomolecular condensate and the site of ribosomal RNA (rRNA) transcription, is implicated in the cellular stress response and in protein quality control. While the exact pathomechanisms of HD remain unclear, the impact of nucleolar dysfunction on HD pathophysiology in vivo is elusive. Here we identified aberrant maturation of rRNA and decreased translational rate in association with human mutant Huntingtin (mHTT) expression. Genetic disruption of nucleolar integrity in vulnerable striatal neurons of the R6/2 HD mouse model decreases mHTT disperse state in the nucleus, exacerbating the motor deficits. The protein nucleophosmin 1 (NPM1), important for nucleolar integrity and rRNA maturation, loses its nucleolar localization. NPM1 de-localization occurs in the striatum and in the skeletal muscle of the progressive zQ175 knock-in HD mouse model, mimicking the phenotype of HD patients in skeletal muscle biopsies. Taken together, we showed that nucleolar integrity regulates the formation of mHTT inclusions in vivo, and identified NPM1 as a novel, readily detectable peripheral histopathological marker of HD progression.

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Mitochondrial hyperfusion: a friend or a foe

Biochemical Society Transactions ◽

10.1042/bst20190987 ◽

2020 ◽

Vol 48 (2) ◽

pp. 631-644 ◽

Cited By ~ 3

Author(s):

Rajdeep Das ◽

Oishee Chakrabarti

Keyword(s):

Negative Impact ◽

Cellular Stress ◽

Cellular Homeostasis ◽

Mitochondrial Population

The cellular mitochondrial population undergoes repeated cycles of fission and fusion to maintain its integrity, as well as overall cellular homeostasis. While equilibrium usually exists between the fission–fusion dynamics, their rates are influenced by organellar and cellular metabolic and pathogenic conditions. Under conditions of cellular stress, there is a disruption of this fission and fusion balance and mitochondria undergo either increased fusion, forming a hyperfused meshwork or excessive fission to counteract stress and remove damaged mitochondria via mitophagy. While some previous reports suggest that hyperfusion is initiated to ameliorate cellular stress, recent studies show its negative impact on cellular health in disease conditions. The exact mechanism of mitochondrial hyperfusion and its role in maintaining cellular health and homeostasis, however, remain unclear. In this review, we aim to highlight the different aspects of mitochondrial hyperfusion in either promoting or mitigating stress and also its role in immunity and diseases.

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