Dataset Information

Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation

ABSTRACT: A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short-lived vertebrate Nothobranchius furzeri combining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein and mRNA mainly due to post-transcriptional mechanisms that account for over 40% of the age-regulated proteins. These changes cause a progressive loss of stoichiometry in several protein complexes, including ribosomes, which show impaired assembly and are enriched in protein aggregates in old brains. Mechanistically, we show that reduction of proteasome activity is an early event during brain aging and is sufficient to induce proteomic signatures of aging and loss of stoichiometry in vivo. Using longitudinal transcriptomic data, we show that the magnitude of early life decline in proteasome levels is the major risk factor for mortality. Our work defines causative events in the aging process that can be targeted to prevent loss of protein homeostasis and delay the onset of age-related neurodegeneration.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Nothobranchius Furzeri

TISSUE(S): Brain

SUBMITTER: Erika Kelmer Sacramento

LAB HEAD: Alessandro Ori

PROVIDER: PXD016459 | Pride | 2020-06-22

REPOSITORIES: Pride

ACCESS DATA

Publications

Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation.

Kelmer Sacramento Erika E Kirkpatrick Joanna M JM Mazzetto Mariateresa M Baumgart Mario M Bartolome Aleksandar A Di Sanzo Simone S Caterino Cinzia C Sanguanini Michele M Papaevgeniou Nikoletta N Lefaki Maria M Childs Dorothee D Bagnoli Sara S Terzibasi Tozzini Eva E Di Fraia Domenico D Romanov Natalie N Sudmant Peter H PH Huber Wolfgang W Chondrogianni Niki N Vendruscolo Michele M Cellerino Alessandro A Ori Alessandro A

Molecular systems biology 20200601 6

A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short-lived vertebrate Nothobranchius furzeri combining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein and mRNA, mainly due to post-transcriptional mechanisms that account for over 40% of the age-regulated proteins. These changes cause ...[more]

PMID: 32558274

Similar Datasets

Project description:This SuperSeries is composed of the following subset Series: GSE24992: Drosophila brain microRNA expression with age: miRNA profiling GSE25007: Drosophila brain gene expression with age: mRNA profiling GSE25008: Drosophila brain gene expression between wildtype and miR-34 null flies Refer to individual Series. Aging is the most prominent risk factor for human neurodegenerative disease, but underlying mechanisms that connect two processes are less well characterized. With age, the brain undergoes functional decline and perhaps degeneration. Such decline may not just contribute to normal aging, but also enhance susceptibility to and progression of age-related neurodegenerative diseases. Therefore, defining intrinsic factors and pathways that underline the normal integrity of the adult nervous system may lead to insights that potentially link aging and neurodegeneration. Here, we report a highly conserved microRNA (miRNA), miR-34, as a modulator of aging and neurodegeneration. Using Drosophila, we show that fly miR-34 expression is brain-enriched and strikingly upregulated with age. Functional studies reveal that, whereas animals without miR-34 are normal as young adults, upon aging, they gradually show late-onset deficits characteristic of accelerated brain aging; these include a transcriptional signature of aged animals, coupled with rapid functional decline, loss of brain integrity, followed by a catastrophic decline in adult viability. Moreover, upregulation of miR-34 protects against neurodegeneration induced by pathogenic human polyglutamine (polyQ) disease protein. We next reveal a dramatic effect of miR-34 to silence the Eip74EF gene of steroid hormone pathways in the adult, which is crucial to maintain the normal aging. Collectively, these data define a miR-34-mediated mechanism that specifically affects long-term integrity of the adult nervous system. miR-34 function in Drosophila may thus present a link that functionally connects aging and neurodegeneration. Our studies implicate essential roles of miRNA- dependent pathways in maintenance of the adult brain, disease pathogenesis and healthy aging.

Dataset Information

Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation

Publications

Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure