Intracellular filamentous inclusions composed of
amyloid-like
proteins are common neuropathological features of many
neurodegenerative disorders. Although the extent of the abnormal
protein pathologies is closely correlated with the
disease progression, little attention has been given to the molecular mechanisms to explain how these pathological
proteins spread. We developed a novel method for introducing
amyloid seeds into cells, and presented experimental evidence of seed-dependent polymerization, leading to the formation of filamentous
protein deposits and cell death. Overexpression of
alpha-synuclein itself does not generate abnormal inclusions, but if fibril seeds are introduced, abundant
alpha-synuclein inclusions positive for PSer129 and
ubiquitin are developed, and the cells undergo cell death. This was also clearly demonstrated in cells expressing different tau
isoforms by introducing the corresponding tau fibril seeds. These results obtained from biochemical analyses of abnormal
proteins in patients strongly suggest that
amyloid-like
proteins, including tau,
alpha-synuclein and TDP-43, propagate from cell to cell and this propagation is the cause of
disease progression, analogously to
metastasis of
cancer cells to multiple different tissues in
cancer progression. From this point of view, I have proposed as a hypothesis that
neurodegenerative diseases with
amyloid-like
proteins can be regarded as "
protein cancers".