Polyglutamine disorders: Pathogenesis and potential drug interventions

Tandon, Shweta; Aggarwal, Prerna; Sarkar, Surajit

doi:10.1016/j.lfs.2024.122562

Cited by 5 publications

(5 citation statements)

References 274 publications

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“…This selective degradation is also found in the human neuropathology of each of the nine diseases (Tandon et al 2024). For an extensive review on polyQ current research and therapeutics, see Tandon et al (2024).…”

Section: Other Diseases Modeled In the Mbmentioning

confidence: 85%

“…Although many screens use S2 cells, or the eye, to investigate aggregation/neurodegeneration, significant loss in the α, β, and γ lobes of the MB has also been observed (Agrawal et al 2005;Zhang et al 2010;Song et al 2013;Tandon and Sarkar 2023). This selective degradation is also found in the human neuropathology of each of the nine diseases (Tandon et al 2024). For an extensive review on polyQ current research and therapeutics, see Tandon et al (2024).…”

Section: Other Diseases Modeled In the Mbmentioning

confidence: 99%

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Modeling neurodegenerative and neurodevelopmental disorders in theDrosophilamushroom body

Stahl,

Tomchik

2024

Learn. Mem.

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The common fruit flyDrosophila melanogasterprovides a powerful platform to investigate the genetic, molecular, cellular, and neural circuit mechanisms of behavior. Research in this model system has shed light on multiple aspects of brain physiology and behavior, from fundamental neuronal function to complex behaviors. A major anatomical region that modulates complex behaviors is the mushroom body (MB). The MB integrates multimodal sensory information and is involved in behaviors ranging from sensory processing/responses to learning and memory. Many genes that underlie brain disorders are conserved, from flies to humans, and studies inDrosophilahave contributed significantly to our understanding of the mechanisms of brain disorders. Genetic mutations that mimic human diseases—such as Fragile X syndrome, neurofibromatosis type 1, Parkinson's disease, and Alzheimer's disease—affect MB structure and function, altering behavior. Studies dissecting the effects of disease-causing mutations in the MB have identified key pathological mechanisms, and the development of a complete connectome promises to add a comprehensive anatomical framework for disease modeling. Here, we reviewDrosophilamodels of human neurodevelopmental and neurodegenerative disorders via the effects of their underlying mutations on MB structure, function, and the resulting behavioral alterations.

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Section: Other Diseases Modeled In the Mbmentioning

confidence: 85%

Section: Other Diseases Modeled In the Mbmentioning

confidence: 99%

Modeling neurodegenerative and neurodevelopmental disorders in theDrosophilamushroom body

Stahl,

Tomchik

2024

Learn. Mem.

View full text Add to dashboard Cite

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“…Another movement/neurodegenerative disorder, Huntington disease (HD) is also caused by CAG repeat expansions. Expanded polyQ proteins from insoluble cellular aggregates [68]. In addition, some ataxia-associated polyQ proteins localize to the nucleolus and may impact nucleolar function [69].…”

Section: Targeting Neurodegeneration Neuroregression and Agingmentioning

confidence: 99%

Polymerase I as a Target for Treating Neurodegenerative Disorders

LeDoux

2024

Preprint

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Polymerase I (Pol I) is at the epicenter of ribosomal RNA (rRNA) synthesis. Pol I is a target for treatment of cancer. Given the many cellular commonalities between cancer and neurodegeneration (i.e., different faces of the same coin) it seems rational to consider targeting of Pol I or, more generally, rRNA synthesis for treatment of disorders associated with the death of terminally differentiated neurons. Principally, ribosomes synthesize proteins and, accordingly, Pol I can be considered the starting point for protein synthesis. Given that cellular accumulation of abnormal proteins such as α-synuclein and tau is an essential feature of neurodegenerative disorders such as Parkinson disease and fronto-temporal dementia, reduction of protein production is now considered as a viable target for treatment of these and closely related neurodegenerative disorders. Abnormalities in polymerase I activity and rRNA production may also be associated with nuclear and nucleolar stress, DNA damage, and childhood onset neuronal death as is the case for the UBTF E210K neuroregression syndrome. Moreover, restraining the activity of Pol I may be a viable strategy to slow aging. Before starting down the road of Pol I inhibition for treating non-cancerous disorders of the nervous system, many questions must be answered. First, how much Pol I inhibition can neurons tolerate and for how long? Should inhibition of Pol I be continuous or pulsed? Will cells compensate for Pol I inhibition by upregulating the number of active rDNAs? At present, we have no effective and safe disease modulatory treatments for Alzheimer disease, α-synucleinopathies, or tauopathies, and novel therapeutic targets and approaches must be explored.

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“…Another movement/neurodegenerative disorder, Huntington disease (HD), is also caused by CAG repeat expansions. Expanded polyQ proteins from insoluble cellular aggregates [78]. In addition, some ataxia-associated polyQ proteins localize to the nucleolus and may impact nucleolar function [79].…”

Section: Targeting Neurodegeneration Neuroregression and Agingmentioning

confidence: 99%

Polymerase I as a Target for Treating Neurodegenerative Disorders

LeDoux

2024

Biomedicines

View full text Add to dashboard Cite

Polymerase I (Pol I) is at the epicenter of ribosomal RNA (rRNA) synthesis. Pol I is a target for the treatment of cancer. Given the many cellular commonalities between cancer and neurodegeneration (i.e., different faces of the same coin), it seems rational to consider targeting Pol I or, more generally, rRNA synthesis for the treatment of disorders associated with the death of terminally differentiated neurons. Principally, ribosomes synthesize proteins, and, accordingly, Pol I can be considered the starting point for protein synthesis. Given that cellular accumulation of abnormal proteins such as α-synuclein and tau is an essential feature of neurodegenerative disorders such as Parkinson disease and fronto-temporal dementia, reduction of protein production is now considered a viable target for treatment of these and closely related neurodegenerative disorders. Abnormalities in polymerase I activity and rRNA production may also be associated with nuclear and nucleolar stress, DNA damage, and childhood-onset neuronal death, as is the case for the UBTF E210K neuroregression syndrome. Moreover, restraining the activity of Pol I may be a viable strategy to slow aging. Before starting down the road of Pol I inhibition for treating non-cancerous disorders of the nervous system, many questions must be answered. First, how much Pol I inhibition can neurons tolerate, and for how long? Should inhibition of Pol I be continuous or pulsed? Will cells compensate for Pol I inhibition by upregulating the number of active rDNAs? At present, we have no effective and safe disease modulatory treatments for Alzheimer disease, α-synucleinopathies, or tauopathies, and novel therapeutic targets and approaches must be explored.

show abstract

Polyglutamine disorders: Pathogenesis and potential drug interventions

Cited by 5 publications

References 274 publications

Modeling neurodegenerative and neurodevelopmental disorders in theDrosophilamushroom body

Modeling neurodegenerative and neurodevelopmental disorders in theDrosophilamushroom body

Polymerase I as a Target for Treating Neurodegenerative Disorders

Polymerase I as a Target for Treating Neurodegenerative Disorders

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