Abstract
Numerous neurodegenerative diseases including prion, Alzheimer’s and Parkinson’s diseases are characterized by accumulation of protein aggregates in brain. Prion disease is unique in that the natively folded prion protein forms diverse misfolded aggregates with distinct molecular conformations (strains), which underlie different disease phenotypes. In addition, the conformational strains are able to self-propagate their unique conformations by recruiting normal protein monomers and converting their conformations to misfolded conformers. There is an increasing body of evidence that suggests other aggregation-prone proteins including tau and α-synuclein associated with Alzheimer’s and Parkinson’s diseases, respectively, also behave like a prion that has conformational strains with self-propagation (seeding) property. Moreover, misfolded protein aggregates can promote misfolding and aggregation of different proteins through cross-seeding, which might be associated with co-occurrence of multiple neurodegenerative diseases in the same patient. Elucidation of diverse conformational strains with self-propagation capability and of molecular basis for the cross-talk between misfolded proteins is essential to the development of effective therapeutic intervention.
Highlights
The hallmark of numerous neurodegenerative diseases is extra- or intra-cellular deposits of misfolded protein aggregates in the central nervous systems (CNS; Sacchettini and Kelly, 2002; Jahn and Radford, 2008; Eisenberg and Jucker, 2012; Knowles et al, 2014; Chiti and Dobson, 2017)
There is mounting evidence that suggests AD and Parkinson’s disease (PD) pathologies are significantly overlapped presumably due to synergistic interactions between tau and α-synuclein, highlighting the complexity of Alzheimer’s diseases and related dementia (ADRD) pathogenesis (Clinton et al, 2010; Moussaud et al, 2014; Castillo-Carranza et al, 2018)
These results indicate that AD and PD pathologies are significantly overlapped presumably due to synergistic interactions between tau and α-synuclein, highlighting the complexity of ADRD pathogenesis
Summary
Numerous neurodegenerative diseases including prion, Alzheimer’s and Parkinson’s diseases are characterized by accumulation of protein aggregates in brain. Prion disease is unique in that the natively folded prion protein forms diverse misfolded aggregates with distinct molecular conformations (strains), which underlie different disease phenotypes. The conformational strains are able to self-propagate their unique conformations by recruiting normal protein monomers and converting their conformations to misfolded conformers. There is an increasing body of evidence that suggests other aggregation-prone proteins including tau and α-synuclein associated with Alzheimer’s and Parkinson’s diseases, respectively, behave like a prion that has conformational strains with self-propagation (seeding) property. Elucidation of diverse conformational strains with self-propagation capability and of molecular basis for the cross-talk between misfolded proteins is essential to the development of effective therapeutic intervention
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