Reducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans

Sharifi, Samim; Chaudhari, Prerana; Martirosyan, Asya; Eberhardt, Alexander Otto; Witt, Finja; Gollowitzer, André; Lange, Lisa; Woitzat, Yvonne; Okoli, Eberechukwu Maryann; Li, Huahui; Rahnis, Norman; Kirkpatrick, Joanna; Werz, Oliver; Ori, Alessandro; Koeberle, Andreas; Bierhoff, Holger; Ermolaeva, Maria

doi:10.1038/s41467-024-46037-w

Cited by 9 publications

(4 citation statements)

References 77 publications

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“…Silent rDNA exists in a closed heterochromatin state whereas active rDNA exists in the euchromatin state. Epigenetic states are controlled by cycle-cell, environmental factors and total rDNA copy number [25,26]. The epigenetics of rDNA regulation in terminally-differentiated neurons is difficult to study and poorly understood.…”

Section: Structure and Function Of Pol Imentioning

confidence: 99%

“…It should also be emphasized that ribosome biogenesis, both normal and aberrant, is energy demanding, which for disorders such as Parkinson disease that have been linked to mitochondrial dysfunction, is particularly undesirable. In this context, it is important to note recent work showing that reducing the metabolic burden of rRNA synthesis promotes longevity in C. elegans [25].…”

Section: Targeting Neurodegeneration Neuroregression and Agingmentioning

confidence: 99%

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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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Section: Structure and Function Of Pol Imentioning

confidence: 99%

Section: Targeting Neurodegeneration Neuroregression and Agingmentioning

confidence: 99%

Polymerase I as a Target for Treating Neurodegenerative Disorders

LeDoux

2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Silent rDNA exists in a closed heterochromatin state, whereas active rDNA exists in the euchromatin state. Epigenetic states are controlled by cycle-cells, environmental factors, and total rDNA copy number [35,36]. The epigenetics of rDNA regulation in terminally differentiated neurons are difficult to study and poorly understood.…”

Section: Structure and Function Of Pol Imentioning

confidence: 99%

“…It should also be emphasized that ribosome biogenesis, both normal and aberrant, is energy demanding, which, for disorders such as Parkinson disease that have been linked to mitochondrial dysfunction, is particularly undesirable. In this context, it is important to note recent work showing that reducing the metabolic burden of rRNA synthesis promotes longevity in C. elegans [35].…”

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.

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Mammalian genome research resources available from the National BioResource Project in Japan

Mizuno-Iijima,

Kawamoto,

Asano

et al. 2024

Mamm Genome

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Mammalian genome research has conventionally involved mice and rats as model organisms for humans. Given the recent advances in life science research, to understand complex and higher-order biological phenomena and to elucidate pathologies and develop therapies to promote human health and overcome diseases, it is necessary to utilize not only mice and rats but also other bioresources such as standardized genetic materials and appropriate cell lines in order to gain deeper molecular and cellular insights. The Japanese bioresource infrastructure program called the National BioResource Project (NBRP) systematically collects, preserves, controls the quality, and provides bioresources for use in life science research worldwide. In this review, based on information from a database of papers related to NBRP bioresources, we present the bioresources that have proved useful for mammalian genome research, including mice, rats, other animal resources; DNA-related materials; and human/animal cells and microbes.

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Reducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans

Cited by 9 publications

References 77 publications

Polymerase I as a Target for Treating Neurodegenerative Disorders

Polymerase I as a Target for Treating Neurodegenerative Disorders

Polymerase I as a Target for Treating Neurodegenerative Disorders

Mammalian genome research resources available from the National BioResource Project in Japan

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