Cell-to-cell transmission mechanism of abnormal protein aggregates:similarities and differences between prion and α-synuclein

Takafumi Hasegawa

Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine

Neurodegeneration-related proteins such as amyloid beta （Aβ） and tau in Alzheimer's disease （AD）, and α-synuclein （αS） in Parkinson's disease （PD） and dementia with Lewy bodies （DLB） share the common property that they become aggregated by physicochemical stress or genetic mutation, leading to inclusion formation inside and outside the cells.　These abnormal protein aggregates are not only pathological hallmarks but also actively participate in the neurodegenerative process.　In prion diseases, normal prion protein （PrP^C） with α-helical structure is converted to a cytotoxic pathogenic form （PrP^Sc） with β-sheet structure by a template of abnormal prion protein.　The newly generated PrP^Sc elicits a chain of conformational changes, resulting in accelerated aggregation.　Furthermore, the PrP^Sc is released outside the cell and infects and invades neighboring cells, causing further structural transformation.　In recent years, mounting evidence has shown that the structural and cell-to-cell transmission analogously observed in prion disease are also observed in neurodegenerative proteins such as AD and PD, and proteins with these transmissible properties are now collectively referred to as “prionoids”.　In this paper, I would like to introduce the similarities and differences between prion and αS, especially in terms of the endocytosis pathway, which is responsible for the transport of cargo molecules inside and outside the cell, and discuss the molecular mechanisms behind the propagation of abnormal proteins.

Address correspondence to Dr. Takafumi Hasegawa, Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine （1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.