Differential response of neurons to autophagy modulation in Huntington’s disease
Huntington’s disease (HD) is caused by the expansion of poly-glutamine repeats in the Huntingtin (Htt) gene and is associated with a wide variety of motor and physiological (sleep, metabolism, etc.) perturbations. Studies from diverse model organisms have proposed that modulation of autophagy (a key...
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| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Autophagy Reports |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/27694127.2025.2519102 |
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| author | Ankit Sharma Sushma Rao Ravi Manjithaya Vasu Sheeba |
| author_facet | Ankit Sharma Sushma Rao Ravi Manjithaya Vasu Sheeba |
| author_sort | Ankit Sharma |
| collection | DOAJ |
| description | Huntington’s disease (HD) is caused by the expansion of poly-glutamine repeats in the Huntingtin (Htt) gene and is associated with a wide variety of motor and physiological (sleep, metabolism, etc.) perturbations. Studies from diverse model organisms have proposed that modulation of autophagy (a key protein homeostatic pathway) can mitigate the toxic effects of mutant HTT protein. However, consistent changes are not observed across studies, and the improvements in phenotypes can be associated with changes in specific circuits/neurons affected by the mutant HTT protein. They suggest that not all neurons respond effectively to autophagy modulation. Hence, it remains to be understood whether diverse circuits/neurons affected by mutant HTT protein respond effectively to this intervention. Using a genetic approach, we expressed mutant HTT protein independently in diverse sets of neurons in male Drosophila melanogaster and asked whether genetic modulation of autophagy pathway through Atg8a overexpression can mitigate the toxic effect of mutant HTT protein. We found that in male flies, not all neurons/circuits expressing mutant HTT protein respond effectively to ATG8a protein. Circadian neurons and neurons regulating carbohydrate and lipid metabolism (Dilp2+ve) showed improvement, while motor and neurons responding to temperature changes showed no improvement. Using cellular markers we also showed that these phenotypes can be attributed to specific changes in mutant HTT and Ref(2)P proteins (autophagy marker). Our study suggests that not all circuits respond effectively to autophagy modulation and suggests a potential cause for low success of autophagy modulators in clinical trials.. |
| format | Article |
| id | doaj-art-18d3825fdbaf4c8b8aaaa94daec6f994 |
| institution | DOAJ |
| issn | 2769-4127 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Autophagy Reports |
| spelling | doaj-art-18d3825fdbaf4c8b8aaaa94daec6f9942025-08-20T03:14:53ZengTaylor & Francis GroupAutophagy Reports2769-41272025-12-014110.1080/27694127.2025.2519102Differential response of neurons to autophagy modulation in Huntington’s diseaseAnkit Sharma0Sushma Rao1Ravi Manjithaya2Vasu Sheeba3Chronobiology and Behavioural Neurogenetics Laboratory, Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, IndiaChronobiology and Behavioural Neurogenetics Laboratory, Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, IndiaAutophagy Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, IndiaChronobiology and Behavioural Neurogenetics Laboratory, Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, IndiaHuntington’s disease (HD) is caused by the expansion of poly-glutamine repeats in the Huntingtin (Htt) gene and is associated with a wide variety of motor and physiological (sleep, metabolism, etc.) perturbations. Studies from diverse model organisms have proposed that modulation of autophagy (a key protein homeostatic pathway) can mitigate the toxic effects of mutant HTT protein. However, consistent changes are not observed across studies, and the improvements in phenotypes can be associated with changes in specific circuits/neurons affected by the mutant HTT protein. They suggest that not all neurons respond effectively to autophagy modulation. Hence, it remains to be understood whether diverse circuits/neurons affected by mutant HTT protein respond effectively to this intervention. Using a genetic approach, we expressed mutant HTT protein independently in diverse sets of neurons in male Drosophila melanogaster and asked whether genetic modulation of autophagy pathway through Atg8a overexpression can mitigate the toxic effect of mutant HTT protein. We found that in male flies, not all neurons/circuits expressing mutant HTT protein respond effectively to ATG8a protein. Circadian neurons and neurons regulating carbohydrate and lipid metabolism (Dilp2+ve) showed improvement, while motor and neurons responding to temperature changes showed no improvement. Using cellular markers we also showed that these phenotypes can be attributed to specific changes in mutant HTT and Ref(2)P proteins (autophagy marker). Our study suggests that not all circuits respond effectively to autophagy modulation and suggests a potential cause for low success of autophagy modulators in clinical trials..https://www.tandfonline.com/doi/10.1080/27694127.2025.2519102Drosophila melanogasterHuntington’s diseaseautophagycircadian rhythmsleepmotor neurons |
| spellingShingle | Ankit Sharma Sushma Rao Ravi Manjithaya Vasu Sheeba Differential response of neurons to autophagy modulation in Huntington’s disease Autophagy Reports Drosophila melanogaster Huntington’s disease autophagy circadian rhythm sleep motor neurons |
| title | Differential response of neurons to autophagy modulation in Huntington’s disease |
| title_full | Differential response of neurons to autophagy modulation in Huntington’s disease |
| title_fullStr | Differential response of neurons to autophagy modulation in Huntington’s disease |
| title_full_unstemmed | Differential response of neurons to autophagy modulation in Huntington’s disease |
| title_short | Differential response of neurons to autophagy modulation in Huntington’s disease |
| title_sort | differential response of neurons to autophagy modulation in huntington s disease |
| topic | Drosophila melanogaster Huntington’s disease autophagy circadian rhythm sleep motor neurons |
| url | https://www.tandfonline.com/doi/10.1080/27694127.2025.2519102 |
| work_keys_str_mv | AT ankitsharma differentialresponseofneuronstoautophagymodulationinhuntingtonsdisease AT sushmarao differentialresponseofneuronstoautophagymodulationinhuntingtonsdisease AT ravimanjithaya differentialresponseofneuronstoautophagymodulationinhuntingtonsdisease AT vasusheeba differentialresponseofneuronstoautophagymodulationinhuntingtonsdisease |