Many neurodegenerative diseases share an enigmatic symmetry, i.e. missense mutations in the gene encoding the disease protein cause a familial variant of the disorder as well as its hallmark brain lesions, but the same brain lesions also form from the corresponding wild type brain protein in sporadic variants of the disease. Moreover, Alzheimer’s disease (AD) is one of the more striking examples of a “triple brain amyloidosis”, i.e. a neurodegenerative disorder wherein at least three different building block proteins (tau, alpha-synuclein) or amyloid beta-peptide fragments (Abeta) of a larger amyloid precursor protein (APP) fibrillize and aggregate into pathological deposits of amyloid within (i.e. neurofibrillary tangles [NFTs] and Lewy bodies [LBs]) and outside (i.e. senile plaques [SPs]) neurons.
However, there are examples of other triple brain amyloidoses such as Down’s Syndrome and Mariana Island dementia or Guam Parkinson’s-dementia Complex that also show evidence of accumulations of amyloid deposits formed by tau, alpha-synuclein and Abeta, and there is increasing recognition that tau or alpha-synuclein intraneuronal inclusions may converge with extracellular deposits of Abeta in “double brain amyloidoses” as exemplified by the abundant tau inclusions in a member of the Contursi kindred with familial Parkinson’s disease (PD), the presence of LBs or NFTs in patients with prion disease, the co-occurrence of PD with abundant Abeta deposits and dementia or LBs with progressive supranuclear palsy in some patients.
Clarification of this enigmatic symmetry in any one of these disorders is likely to have a profound impact on understanding the mechanisms that underlie other of these diseases as well as on efforts to develop novel therapies to treat them. For this reason, this paper by Cummings is important because if focuses on shared underlying mechanisms common to these and other disorders including the different types of brain amyloid that are characteristic of each of these diseases as well as cellular mechanisms that may promote or inhibit accumulations of protein aggregates (oxidative stress, proteosome/ubiquitin systems, chaperone/heat shock protein responses, genetic mutations, etc.) with the expectation that insights into these mechanism will accelerate the pace of the successful discovery of drugs to treat these neurodegenerative brain amyloidoses .
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University of Pennsylvania
Many neurodegenerative diseases share an enigmatic symmetry, i.e. missense mutations in the gene encoding the disease protein cause a familial variant of the disorder as well as its hallmark brain lesions, but the same brain lesions also form from the corresponding wild type brain protein in sporadic variants of the disease. Moreover, Alzheimer’s disease (AD) is one of the more striking examples of a “triple brain amyloidosis”, i.e. a neurodegenerative disorder wherein at least three different building block proteins (tau, alpha-synuclein) or amyloid beta-peptide fragments (Abeta) of a larger amyloid precursor protein (APP) fibrillize and aggregate into pathological deposits of amyloid within (i.e. neurofibrillary tangles [NFTs] and Lewy bodies [LBs]) and outside (i.e. senile plaques [SPs]) neurons.
However, there are examples of other triple brain amyloidoses such as Down’s Syndrome and Mariana Island dementia or Guam Parkinson’s-dementia Complex that also show evidence of accumulations of amyloid deposits formed by tau, alpha-synuclein and Abeta, and there is increasing recognition that tau or alpha-synuclein intraneuronal inclusions may converge with extracellular deposits of Abeta in “double brain amyloidoses” as exemplified by the abundant tau inclusions in a member of the Contursi kindred with familial Parkinson’s disease (PD), the presence of LBs or NFTs in patients with prion disease, the co-occurrence of PD with abundant Abeta deposits and dementia or LBs with progressive supranuclear palsy in some patients.
Clarification of this enigmatic symmetry in any one of these disorders is likely to have a profound impact on understanding the mechanisms that underlie other of these diseases as well as on efforts to develop novel therapies to treat them. For this reason, this paper by Cummings is important because if focuses on shared underlying mechanisms common to these and other disorders including the different types of brain amyloid that are characteristic of each of these diseases as well as cellular mechanisms that may promote or inhibit accumulations of protein aggregates (oxidative stress, proteosome/ubiquitin systems, chaperone/heat shock protein responses, genetic mutations, etc.) with the expectation that insights into these mechanism will accelerate the pace of the successful discovery of drugs to treat these neurodegenerative brain amyloidoses .
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