TY - JOUR
T1 - Inhibitors of α-synuclein oligomerization and toxicity
T2 - A future therapeutic strategy for Parkinson's disease and related disorders
AU - Amer, Dena A.M.
AU - Irvine, G. Brent
AU - El-Agnaf, Omar M.A.
PY - 2006/8
Y1 - 2006/8
N2 - An abundance of genetic, histopathological, and biochemical evidence has implicated the neuronal protein, α-synuclein (α-syn) as a key player in the development of several neurodegenerative diseases, the so-called synucleinopathies, of which Parkinson's disease (PD) is the most prevalent. Development of disease appears to be linked to events that increase the intracellular concentration of α-syn or cause its chemical modification, either of which can accelerate the rate at which it forms aggregates. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or altered forms of α-syn, such as truncations, missense mutations, or chemical modifications by oxidative reactions. Aggregated forms of the protein, especially newly formed soluble aggregates, are toxic to cells, so that one therapeutic strategy would be to reduce the rate at which such oligomerization occurs. We have therefore designed several peptides and also identified small molecules that can inhibit α-syn oligomerization and toxicity in vitro. These compounds could serve as lead compounds for the design of new drugs for the treatment of PD and related disorders in the future.
AB - An abundance of genetic, histopathological, and biochemical evidence has implicated the neuronal protein, α-synuclein (α-syn) as a key player in the development of several neurodegenerative diseases, the so-called synucleinopathies, of which Parkinson's disease (PD) is the most prevalent. Development of disease appears to be linked to events that increase the intracellular concentration of α-syn or cause its chemical modification, either of which can accelerate the rate at which it forms aggregates. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or altered forms of α-syn, such as truncations, missense mutations, or chemical modifications by oxidative reactions. Aggregated forms of the protein, especially newly formed soluble aggregates, are toxic to cells, so that one therapeutic strategy would be to reduce the rate at which such oligomerization occurs. We have therefore designed several peptides and also identified small molecules that can inhibit α-syn oligomerization and toxicity in vitro. These compounds could serve as lead compounds for the design of new drugs for the treatment of PD and related disorders in the future.
KW - Amyloid fibrils
KW - Beta-sheet breaker peptides
KW - Drug discovery
KW - Neurodegenerative diseases
KW - α-Synuclein
UR - http://www.scopus.com/inward/record.url?scp=33747607074&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33747607074&partnerID=8YFLogxK
U2 - 10.1007/s00221-006-0539-y
DO - 10.1007/s00221-006-0539-y
M3 - Article
C2 - 16733698
AN - SCOPUS:33747607074
SN - 0014-4819
VL - 173
SP - 223
EP - 233
JO - Experimental Brain Research
JF - Experimental Brain Research
IS - 2
ER -