Juvenile and adult expression of polyglutamine expanded huntingtin produce distinct aggregate distributions in<i>Drosophila</i>muscle

Barwell, Taylor; Raina, Sehaj; Page, Austin; MacCharles, Hayley; Seroude, Laurent

doi:10.1093/hmg/ddad098

Cited by 5 publications

(2 citation statements)

References 63 publications

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“…HD is characterized by muscle dysfunction, and we have previously found that Htt-PQ72 causes dysfunction in cardiac and skeletal muscle ( Melkani et al, 2013 ; Barwell et al, 2023 ). It has been proposed that this peripheral muscle dysfunction is primarily caused by peripheral expression of mutant huntingtin, and that peripheral mutant huntingtin could cause neuronal dysfunction in the brain ( Chuang and Demontis, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila

Roth,

Moraes,

et al. 2023

Front. Aging Neurosci.

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Huntington’s disease (HD) is a neurodegenerative disease characterized by movement and cognitive dysfunction. HD is caused by a CAG expansion in exon 1 of the HTT gene that leads to a polyglutamine (PQ) repeat in the huntingtin protein, which aggregates in the brain and periphery. Previously, we used Drosophila models to determine that Htt-PQ aggregation in the heart causes shortened lifespan and cardiac dysfunction that is ameliorated by promoting chaperonin function or reducing oxidative stress. Here, we further study the role of neuronal mutant huntingtin and how it affects peripheral function. We overexpressed normal (Htt-PQ25) or expanded mutant (Htt-PQ72) exon 1 of huntingtin in Drosophila neurons and found that mutant huntingtin caused age-dependent Htt-PQ aggregation in the brain and could cause a loss of synapsin. To determine if this neuronal dysfunction led to peripheral dysfunction, we performed a negative geotaxis assay to measure locomotor performance and found that neuronal mutant huntingtin caused an age-dependent decrease in locomotor performance. Next, we found that rapamycin reduced Htt-PQ aggregation in the brain. These results demonstrate the role of neuronal Htt-PQ in dysfunction in models of HD, suggest that brain-periphery crosstalk could be important to the pathogenesis of HD, and show that rapamycin reduces mutant huntingtin aggregation in the brain.

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Section: Resultsmentioning

confidence: 99%

Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila

Roth,

Moraes,

et al. 2023

Front. Aging Neurosci.

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“…30 In Drosophila, expression of human genes with expanded polyglutamine repeats recapitulates human disease pathology such as polyglutamine aggregates, neurodegeneration, dendrite defects, cytoskeletal aberrations, cell type-specific toxicity, behavioral defects, and RNA toxicity. [31][32][33][34][35][36][37][38][39][40][41] In this paper we use Drosophila models for SCA1, SCA2, SCA3 and HD to study regeneration in the context of neurodegenerative disease. 31,34,40,42 Here we show that degenerating neurons are capable of dendrite regeneration.…”

Section: Introductionmentioning

confidence: 99%

Dendrite injury, but not axon injury, triggers neuroprotection in Drosophila models of neurodegenerative disease

Prange,

Bhakta,

Sysoeva

et al. 2024

Preprint

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Dendrite defects and loss are early cellular alterations observed across neurodegenerative diseases that play a role in early disease pathogenesis. Dendrite degeneration can be modeled by expressing pathogenic polyglutamine disease transgenes in Drosophila neurons in vivo. Here, we show that we can protect against dendrite loss in neurons modeling neurodegenerative polyglutamine diseases through injury to a single primary dendrite branch. We find that this neuroprotection is specific to injury-induced activation of dendrite regeneration: neither injury to the axon nor injury just to surrounding tissues induces this response. We show that the mechanism of this regenerative response is stabilization of the actin (but not microtubule) cytoskeleton. We also demonstrate that this regenerative response may extend to other neurodegenerative diseases. Together, we provide evidence that activating dendrite regeneration pathways has the potential to slow or even reverse dendrite loss in neurodegenerative disease.

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Dendrite injury triggers neuroprotection in Drosophila models of neurodegenerative disease

Prange,

Bhakta,

Sysoeva

et al. 2024

Sci Rep

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Dendrite defects and loss are early cellular alterations observed across neurodegenerative diseases that play a role in early disease pathogenesis. Dendrite degeneration can be modeled by expressing pathogenic polyglutamine disease transgenes in Drosophila neurons in vivo. Here, we show that we can protect against dendrite loss in neurons modeling neurodegenerative polyglutamine diseases through injury to a single primary dendrite branch. We find that this neuroprotection is specific to injury-induced activation of dendrite regeneration: neither injury to the axon nor injury just to surrounding tissues induces this response. We show that the mechanism of this regenerative response is stabilization of the actin (but not microtubule) cytoskeleton. We also demonstrate that this regenerative response may extend to other neurodegenerative diseases. Together, we provide evidence that activating dendrite regeneration pathways has the potential to slow–or even reverse–dendrite loss in neurodegenerative disease.

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Juvenile and adult expression of polyglutamine expanded huntingtin produce distinct aggregate distributions inDrosophilamuscle

Cited by 5 publications

References 63 publications

Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila

Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila

Dendrite injury, but not axon injury, triggers neuroprotection in Drosophila models of neurodegenerative disease

Dendrite injury triggers neuroprotection in Drosophila models of neurodegenerative disease

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