Backgrounds

Many neurodegenerative diseases are associated with intracellular accumulation of abnormal amyloid-like proteins, including tau in Alzheimer’s disease (AD), alpha-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 correlates with clinical presentation and disease progression.

We have been studying these disease-associated proteins using immuno-histochemical, ultrastructural, and biochemical methods. In collaboration with the groups of Michel Goedert, Sjors Scheres, and Benjamin Ryskeldi-Falcon in MRC LMB, we have determined the structures of pathological tau, alpha-synuclein, and TDP-43 filaments extracted from patient brains. We have found that these proteins have characteristic folding structures that form unique amyloid-like filaments in different diseases. This indicates that different folding variants of the same protein can cause different diseases and that structural analysis of pathological proteins is useful for disease classification.

Objectives

• To perform neuropathological and biochemical analysis on post-mortem brain tissue to elucidate molecular pathogenesis
• To create test tube, cellular, and animal models to reproduce patient pathologies and develop drugs and treatments that will be able to suppress the progression of disease
• To elucidate the mechanisms of a propagation hypothesis proposed by the project team

Members

Project Leader Takashi Nonaka

• Genjiro Suzuki
• Naomi Nihonmatsu
• Masami Suzukake
• Yoshiki Takamatsu
• Airi Tarutani
• Shotaro Shimonaka