Research: Aging and evolution
The problem
We have built Parkinson’s models in medaka and zebrafish by drugs and genome editing. They helped us understand pathology, but models of sporadic disease — the majority of patients — remain hard. So we asked: what does the brain do in an old age that natural selection has never seen?
What we found
Fish diversity is an advantage. Fish in short-lived African rain pools die when the water dries. They persist as drought-resistant eggs, so longevity was not selected, and they are among the shortest-lived vertebrates. In the African turquoise killifish, aging alone produced dopaminergic degeneration and α-synuclein accumulation resembling human Parkinson’s disease (Cell Reports, 2019). Detailed post-translational analysis of α-synuclein in fish and human brain identified T64 phosphorylation, which disrupts oligomer formation and is toxic (PNAS, 2023).
Papers: Matsui et al., Cell Rep., 2019. doi:10.1016/j.celrep.2019.01.015
Matsui et al., Proc. Natl. Acad. Sci. USA, 2023. doi:10.1073/pnas.2214652120 / Press release (PDF)
Models and the link to human aging
We are pursuing pathology and omics of aging and age-related disease in this killifish, aiming at insights that apply to humans and other life. We were among the first in Japan to breed them stably, and we use them for pathogenesis of age-related disease with an approach distinct from much overseas aging research.
Questions to take forward.
Aging
Question Where does aging end and disease begin?
What we have found The turquoise killifish develops dopaminergic degeneration and α-synuclein accumulation with age alone (Cell Reports, 2019). Post-translational analysis in fish and human brain identified T64 phosphorylation and its toxicity (PNAS, 2023). Our view is that aging is the base of age-related disease, and that a further vicious cycle is what turns it into disease.
What we want to ask next
- Can we stop disease without stopping aging? And why do we age at all?
Approaches We compare killifish ages by pathology, omics, imaging and behaviour. Zebrafish and cultured cells are used when a mechanism needs to be isolated. With the required approvals, findings from cells and animals are then tested in human tissue.
Who might start here A starting point if you care about aging biology, comparative pathology or omics. Prior fish-husbandry experience is not required.
- Matsui, H.*, Kenmochi, N., Namikawa, K. Age- and α-Synuclein-Dependent Degeneration of Dopamine and Noradrenaline Neurons in the Annual Killifish Nothobranchius furzeri. Cell Rep. 2019. doi:10.1016/j.celrep.2019.01.015
- Matsui, H.*, Ito, S., Matsui, H., Ito, J., Gabdulkhaev, R., Hirose, M., Yamanaka, T., Koyama, A., Kato, T., Tanaka, M., Uemura, N., Matsui, N., Hirokawa, S., Yoshihama, M., Shimozawa, A., Kubo, S., Iwasaki, K., Hasegawa, M., Takahashi, R., Hirai, K., Kakita, A., Onodera, O. Phosphorylation of α-synuclein at T64 results in distinct oligomers and exerts toxicity in models of Parkinson's disease. Proc. Natl. Acad. Sci. USA. 2023. doi:10.1073/pnas.2214652120
Evolution
Question What are the evolutionary origins of brain disease, developmental disorders, or aging?
What we have found Alpha-synuclein, the molecule implicated in Parkinson’s disease, first appeared in fish. Amyloid precursor protein exists in fish and insects through evolution. The turquoise killifish develops a Parkinson-like state during aging (Cell Reports, 2019).
What we want to ask next
- Why has life kept disease-causing molecules for hundreds of millions of years? And why have disabilities persisted to this day?
- Wild animals also develop brain disease. Why have the mechanisms behind it escaped natural selection?
Approaches We bring together cells, fishes and mice, modern neuropathology and evolutionary methods, and the BRI brain bank.
Who might start here A starting point if you care about evolution, comparative biology, or the origins of disease.
- Matsui, H.*, Kenmochi, N., Namikawa, K. Age- and α-Synuclein-Dependent Degeneration of Dopamine and Noradrenaline Neurons in the Annual Killifish Nothobranchius furzeri. Cell Rep. 2019. doi:10.1016/j.celrep.2019.01.015
Discuss research opportunities
Projects develop through discussion, starting from the lab’s research strengths and your interests and experience. We value researchers who learn from their results, refine the question and help shape the direction of their work.