Dementia Research Project
Elucidation of the molecular mechanisms of dementia and the development of novel treatments and preventive methods
Research Summary
Many neurodegenerative diseases are associated with intracellular amyloid-like protein pathologies, such as tau in Alzheimer’s disease (AD), α-synuclein in dementia with Lewy bodies (DLB) and TDP-43 in amyotrophic lateral sclerosis (ALS) and frontotemporal dementias (FTD). Importantly, the distribution and spread of these proteins closely correlates with clinical presentation and disease progression.
We have been investigating these intracellular pathological proteins prepared in these diseases, immuno-histochemically, ultrastructurally, and biochemically using liquid chromatography with tandem mass spectrometry (LC/MS/MS).
In collaboration with Michel Goedert and Sjors Scheres in LMB and the Japan brain bank network (JBBN), we determined the structures of pathological tau and alpha-synuclein filaments from brains of patients with corticobasal degeneration (CBD) and multiple system atrophy. We further identified numerous post-translational modifications in these filamentous assemblies. We demonstrated that injection of aggregate recombinant tau filaments into wild-type mice seeded the aggregation of endogenous murine tau, leading to the spread of aggregates into distinct brain areas. In addition, we generated two different types of alpha--synuclein fibrils from identical wild-type alpha--synuclein monomers under different conditions and showed that these fibrils have different prion-like ablilities to convert endogenous soluble alpha--synuclein monomers into amyloid-like fibrils.
Selected Publications
- Yang Y, et al. (2022) “Structures of α-synuclein filaments from human brains with Lewy pathology”. Nature. 610(7933):791-795.
- Schweighauser M, et al. (2022) “Age-dependent formation of TMEM106B amyloid filaments in human brains”. Nature. 605(7909):310-3148.
- Arseni D, Hasegawa M, et al. (2022) “Structures of TDP-43 filaments from amyotrophic 1 lateral sclerosis with frontotemporal lobar degeneration”. Nature 601(7891):139-143.
- Tarutani A, et al. (2022) Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43. Acta Neuropathol. 143(6):613-640.
- Tarutani A, et al. (2021) “Human tauopathy-derived tau strains determine the substrates recruited for templated amplification.” Brain. Sep 4;144(8):2333-2348.
- Hosokawa M, et al. (2021) “Development of a novel tau propagation mouse model endogenously expressing 3 and 4 repeat tau isoforms.” Brain. Sep 13:awab289.
- Shi Y, et al. (2021) “Structure-based classification of tauopathies.” Nature. Sep 29. Online ahead of print. (Oct.14)
- Zhang W, et al. Novel tau filament fold in corticobasal degeneration. Nature 2020 Apr;580(7802):283-287.
- Masuda-Suzukake M, et al. Dextran sulphate-induced tau assemblies cause endogenous tau aggregation and propagation in wild-type mice. Brain Communications 2020 Jul 8;2(2):fcaa091.
- Suzuki G, et al. α-Synuclein strains that cause distinct pathologies differentially inhibit proteasome. eLife. 2020 Jul 22;9:e56825.
- Schweighauser M, et al. Structures of α-synuclein filaments from multiple system atrophy. Nature 2020 Sep; 585(7825):464-469 .