2023 Fiscal Year Final Research Report
Axonal RNA study based on Dying back hypothesis for novel factors involved in motor neuron selective degeneration of Amyotrophic Lateral Sclerosis.
| Project/Area Number |
20K16593
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52020:Neurology-related
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| Research Institution | Tohoku University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2024-03-31
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| Keywords | 筋萎縮性側索硬化症 / TARDBP / TDP-43 / iPS細胞 / 運動ニューロン選択的変性 / PHOX2B |
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| Outline of Final Research Achievements |
Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive and fatal neurodegenerative disease that causes generalized muscle weakness and atrophy, breathing and swallowing dysfunction. To elucidate the cause of selective degeneration of motor neurons in ALS, induced pluripotent stem cells (iPS cells) from TARDBP mutant ALS patients were differentiated to motor neurons (iMNs). Axon fractionated RNA sequencing (RNA-Seq) of iMNs revealed PHOX2B, which is down-regulated in the mutant axons and involved in neurite outgrowth.
Furthermore, we compared the RNA expression of iMNs with iPS cells derived autonomic neurons, which were rich in PHOX2B and maintained in ALS late-stage. Some downstream target candidate genes of PHOX2B have narrowed down.
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| Free Research Field |
神経変性疾患
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| Academic Significance and Societal Importance of the Research Achievements |
筋萎縮性側索硬化症（ALS）は成人発症難治性進行性の致死的な神経変性疾患である。病態は未解明で根本的治療法はない。
PHOX2BはALSで発症後長期まで保たれる自律神経等に多く含まれるが、これまでALSとの関連が指摘されていなかった。PHOX2Bの下流に位置する治療標的を見出すことは、ALS病態解明と新規治療法開発につながると考える。さらにPHOX2B mRNAはTARDBP mRNAやそのタンパクTDP-43との相互作用や結合が確認され、PHOX2B下流の治療標的研究は、患者病理でみられるような細胞内TDP-43異常凝集をきたす神経筋疾患群の病態研究にも貢献する可能性がある。
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