Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta
| Autor: | Jan Gruber, Sudharshan Ravi, Markus R. Wenk, Jean-Paul Kovalik, Philip K. Moore, Hyung-Seok Kim, Nicholas S. Tolwinski, Amaury Cazenave-Gassiot, Jianhong Ching, Diogo Barardo, Sheng Fong, Rudiyanto Gunawan, Barry Halliwell, Emelyne Teo, Tsze Yin Tan |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
QH301-705.5
Amyloid beta Science Transgene Protein aggregation Mitochondrion General Biochemistry Genetics and Molecular Biology Transcriptome 03 medical and health sciences 0302 clinical medicine medicine Biology (General) Beta (finance) TCA cycle Caenorhabditis elegans 030304 developmental biology chemistry.chemical_classification 0303 health sciences General Immunology and Microbiology biology General Neuroscience General Medicine medicine.disease biology.organism_classification 3. Good health Cell biology amyloid beta mitochondria Citric acid cycle Enzyme chemistry biology.protein Medicine Alzheimer's disease metformin metabolism 030217 neurology & neurosurgery |
| Zdroj: | eLife, 8 eLife, Vol 8 (2019) |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.50069 |
| Popis: | Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on a deeper analysis of these metabolic changes associated with Aβ-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics, biochemical studies and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aβ expression. In particular, GRU102 show reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects are associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurs before any significant increase in global protein aggregate is detectable. Treatment with an antidiabetes drug, Metformin, reverses Aβ-induced metabolic defects, reduces protein aggregation and normalizes the lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in AD pathology and a promising target for intervention. |
| Databáze: | OpenAIRE |
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