Research study reveals depletion of mitochondria in neuron axons leads to protein accumulation, an essential factor in neurodegenerative illness, providing a new target for treatment. Credit: SciTechDaily.comKey path recognized for how exhaustion of axonal mitochondria interferes with autophagy.Researchers from Tokyo Metropolitan University have actually recognized how proteins gather abnormally in neurons, a feature of neurodegenerative diseases like Alzheimers. They utilized fruit flies to reveal that depletion of mitochondria in axons can directly cause protein accumulation. At the exact same time, significantly high amounts of a protein called eIF2β were discovered. Restoring the levels to normal led to a recovery in protein recycling. Such findings guarantee new treatments for neurodegenerative diseases.The Cellular Factory: Protein Production and DisassemblyEvery cell in our bodies is a hectic factory, where proteins are continuously being produced and taken apart. Any modifications or lapses in either the production or recycling stages can lead to major illnesses. Neurodegenerative illness such as Alzheimers and Amyotrophic Lateral Sclerosis (ALS), for example, are known to be accompanied by an abnormal accumulation of proteins in nerve cells. However, the trigger behind this build-up remains unknown.As axonal mitochondria are lost, changes in the subunits of eIF2 are seen which hamper translation and autophagy and trigger the accumulation of proteins in cells. Credit: Tokyo Metropolitan UniversityResearch Using Drosophila Fruit FliesA team led by Associate Professor Kanae Ando of Tokyo Metropolitan University has actually been trying to figure out the reasons for abnormal protein build-up by studying Drosophila fruit flies, a frequently studied design organism that has numerous essential resemblances with human physiology.They concentrated on the existence of mitochondria in axons, the long tendril-like appendages that extend of neurons and form the needed connections that enable signals to be transmitted inside our brains. It is known that the levels of mitochondria in axons can drop with age, and throughout the development of neurodegenerative diseases.Findings on Mitochondria Depletion and Protein AccumulationNow, the group has discovered that the exhaustion of mitochondria in axons has a direct bearing on protein accumulation. They used genetic engineering to reduce the production of milton, a key protein in the transport of mitochondria along axons.It was discovered that this caused unusual levels of protein developing in fruit fly nerve cells, an outcome of the breakdown of autophagy, the recycling of proteins in cells.Through proteomic analysis, they were able to determine a significant upregulation in eIF2β, a key subunit of the eIF2 protein complex responsible for the initiation of protein production (or translation). The eIF2α subunit was also found to be chemically customized. Both of these issues hamper the healthy action of eIF2.Implications for Neurodegenerative Disease TreatmentImportantly, by artificially reducing levels of eIF2β, the group discovered that they could restore the autophagy that was lost and restore some of the nerve cell function that was impaired due to axonal mitochondria loss. This not only reveals that exhaustion of mitochondria in axons can cause irregular protein accumulation, but that this happens via upregulation of eIF2β.As populations age and the frequency of neurodegenerative conditions continues to increase, the groups findings present a crucial action in establishing treatments to combat these severe illnesses.Reference: “Axonal distribution of mitochondria preserves neuronal autophagy throughout aging by means of eIF2β” by Kanako Shinno, Yuri Miura, Koichi M. Iijima, Emiko Suzuki and Kanae Ando, 25 March 2024, eLife.DOI: 10.7554/ eLife.95576.1 This work was supported by a Sasakawa Scientific Research Grant (2021-4087), the Takeda Science Foundation, a Hoansha Foundation Grant, a research study award from the Japan Foundation for Aging and Health and the Novartis Foundation (Japan) for the Promotion of Science, a Grant-in-Aid for Scientific Research on Challenging Research (Exploratory) [JSPS KAKENHI Grant Number 19K21593], NIG-JOINT (National Institute of Genetics, 71A2018, 25A2019), and the TMU Strategic Research Fund for Social Engagement.
Such findings guarantee new treatments for neurodegenerative diseases.The Cellular Factory: Protein Production and DisassemblyEvery cell in our bodies is a busy factory, where proteins are continuously being produced and dismantled. It is understood that the levels of mitochondria in axons can drop with age, and throughout the development of neurodegenerative diseases.Findings on Mitochondria Depletion and Protein AccumulationNow, the group has actually discovered that the exhaustion of mitochondria in axons has a direct bearing on protein accumulation. They utilized genetic modification to reduce the production of milton, a key protein in the transportation of mitochondria along axons.It was discovered that this led to abnormal levels of protein developing up in fruit fly nerve cells, an outcome of the breakdown of autophagy, the recycling of proteins in cells.Through proteomic analysis, they were able to determine a significant upregulation in eIF2β, a crucial subunit of the eIF2 protein complex responsible for the initiation of protein production (or translation).
