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Transmission of misfolded proteins in neurodegenerative disorders: A common mechanism of disease progression| old_uid | 12754 |
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| title | Transmission of misfolded proteins in neurodegenerative disorders: A common mechanism of disease progression |
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| start_date | 2013/09/09 |
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| schedule | 11h |
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| online | no |
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| summary | The accumulation of misfolded proteins is a fundamental pathogenic process in neurodegenerative diseases. These hallmark proteinaceous lesions include extracellular senile plaques comprised of the AB peptide and intracellular neurofibrillary tangles consisted of tau proteins in Alzheimer’s disease as well as x-synuclein (x-syn) containing Lewy bodies and Lewy neurites in Parkinson’s disease. We hypothesized that templated recruitment of endogenous proteins by misfolded conformers follow by cell-to-cell spreading of the pathology are a common disease mechanism that account for the progression of these age-related disorders. In both tauopathies and synucleinopathies, we demonstrate that pre-formed fibrils (pffs) generated from recombinant tau or x-syn enters cultured primary neurons as well as transgenic and wildtype mice, promoted recruitment of soluble endogenous proteins into insoluble protein aggregates resembling the pathology in their human counterparts. Pathologic misfolded aggregates propagated along major central nervous system (CNS) pathways to regions far beyond injection sites and appear to follow neuroanatomical interconnectomes. Thus, synthetic x-Syn or tau pffs are wholly sufficient to initiate neurodegenerative disease pathology and transmit disease in primary neurons in vitro and in mice in vivo. Thus, these data support a prion-like cascade in neurodegenerative disease protein spreading whereby cell-to-cell transmission and propagation of misfolded proteins underlie the CNS proliferation of disease pathology. These findings open up new avenues for understanding the progression of neurodegenerative diseases and for developing novel therapeutics. |
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| responsibles | Agid |
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