Molecular mechanisms of pathological protein propagation and its regulation

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Progressive neurodegeneration with accumulation of abnormal proteins is the defining neuropathological feature of many neurodegenerative diseases, including Lewy body disease (LBD) and ALS/FTLD. We revealed that injections of recombinant alpha-synuclein (aS) fibrils efficiently induced hyperphosphorylated aS pathology in wild-type mice. Biochemical analyses demonstrated that endogenous mouse aS started to accumulate 3 months after inoculation. Furthermore, injections of Sarkosyl-insoluble aS from LBD patients induced similar aS pathology, indicating that aS fibrils show prion-like infectivity. We also demonstrated that insoluble TDP-43 has prion-like properties. These results indicate that pathological proteins may play a role in the progression of neurodegenerative diseases with protein pathologies. These cellular and mouse models should be useful for elucidating progression mechanisms and evaluating disease-modifying therapy.