Endowed Chair

Neurotherapeutics

Interdisciplinary approach to target intractable neurodegenerative diseases and dementia
  • Elucidation of pathomechanisms of neurodegenerative diseases with focus on structural abnormalities, aggregation, and propagation of proteins and RNA
  • Development of molecular-targeted therapy for neurodegenerative diseases by screening for protein aggregation inhibitors
  • Development of biomarkers of neurodegenerative diseases with focus on exosomes
  • Elucidation of mechanisms involving repeat associated non-ATG initiated translation and its pathomechanisms
  • The largest neurodegenerative disease Drosophila model Bank in Japan, and nationwide collaborative research and enrollment of students

Pathomechanism and therapeutic research of neurodegenerative diseases using various technologies; from structural analysis of proteins and RNA to cultured cells and animal models

As global aging of the population is advancing, a number of patients suffering from neurodegenerative diseases is increasing such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and polyglutamine diseases such as Huntington’s disease, spinocerebellar ataxia (SCA), etc. These intractable diseases all lack effective therapeutic treatments and diagnostic methods. Research in our laboratory focuses on dementia, with the aim to provide even to elderly a high quality of life and a healthy future.

In recent years, it has been proposed that the accumulation of misfolded proteins such as amyloid β, tau, α-synuclein, TDP-43, polyglutamine, etc., in the brain is a common molecular mechanism that triggers the onset of many neurodegenerative diseases. More recently, a totally new mechanism has been discovered in some cases of spinocerebellar ataxias and amyotrophic lateral sclerosis; repeat associated non-ATG initiated translation (RAN translation) that translates abnormal peptides from abnormal repeat RNA as a template. This theory has drawn attention to the relationship between neurodegenerative diseases and abnormal RNAs.

(Figure 1)

We aim to elucidate the pathology of neurodegenerative diseases, develop biomarkers and therapeutic methods, and focus on the misfolding and aggregation of proteins and RNA. Our laboratory consists of researchers from medical, pharmaceutical, science and agricultural backgrounds. Our research encompasses a number of in vitro studies such as protein structural analysis and molecular cell biological analysis, in vivo disease models such as Drosophila, mouse and marmoset, and compound screening methods etc.

To date, in regards to abnormal polyglutamine protein, we have identified the mechanism of cytotoxicity resulting from β-sheet conformational transition [1], inhibition of neurodegeneration by polyglutamine-binding peptide QBP1 [2, 3], non-cell autonomous suppression of neurodegeneration by intercellular chaperone transmission via exosomes [4]. We also found the promotion of prion-like conformational change of α-synuclein by association with glycolipid implicated in Parkinson’s disease [5], and recently, discovered a novel mechanism of repeat associated translation and neurodegeneration in SCA31 [6]. Based on these findings, we aim to develop molecular-targeted therapies by using aggregation inhibitor peptides and compounds as well as to search for biomarkers by focusing on exosomes. We also aim to elucidate the mechanism of neurodegeneration caused by abnormal RNA and RAN translation. We are also investigating the impact of environmental factors on these mechanisms.

【References】

1. Nagai et al. Nat Struct Mol Biol 14(4): 332 – 340, 2007.
2. Nagai et al. Hum Mol Genet 12(11): 1253-9, 2003.
3. Popiel et al. Mol Ther 15(2): 303-9, 2007.
4. Takeuchi et al. PNAS 112(19): E2497–E2506, 2015.
5. Suzuki et al. Hum Mol Genet 24(23): 6675-86, 2015.
6. Ishiguro et al. Neuron, in press.