TY - JOUR
T1 - A precipitating role for truncated α-synuclein and the proteasome in α-synuclein aggregation
T2 - Implications for pathogenesis of parkinson disease
AU - Liu, Chang Wei
AU - Giasson, Benoit I.
AU - Lewis, Karen A.
AU - Lee, Virginia M.
AU - DeMartino, George N.
AU - Thomas, Philip J.
PY - 2005/6/17
Y1 - 2005/6/17
N2 - Parkinson disease and other α-synucleinopathies are characterized by the deposition of intraneuronal α-synuclein (αSyn) inclusions. A significant fraction (about 15%) of αSyn in these pathological structures are truncated forms that have a much higher propensity than the full-length αSyn to form aggregates in vitro. However, little is known about the role of truncated αSyn species in pathogenesis or the means by which they are generated. Here, we have provided an in vitro mechanistic study demonstrating that truncated αSyns induce rapid aggregation of full-length protein at substoichiometric ratios. Co-overexpression of truncated αSyn with full-length protein increases cell vulnerability to oxidative stress in dopaminergic SH-SY5Y cells. These results suggest a precipitating role for truncated αSyn in the pathogenesis of diseases involving αSyn aggregation. In this regard, the A53T mutation found in some cases of familial Parkinson disease exacerbates the accumulation of insoluble αSyns that correlates with the onset of pathology in transgenic mice expressing human αSyn-A53T mutant. The caspase-like activity of the 20 S proteasome produces truncated fragments similar to those found in patients and animal models from degradation of unstructured αSyn. We propose a model in which incomplete degradation of αSyn, especially under overloaded proteasome capacity, produces highly amyloidogenic fragments that rapidly induce the aggregation of full-length protein. These aggregates in turn reduce proteasome activity, leading to further accumulation of fragmented and full-length αSyns, creating a vicious cycle of cytotoxicity. This model has parallels in other neurodegenerative diseases, such as Huntington disease, where coaggregation of poly(Q) fragments with full-length protein has been observed.
AB - Parkinson disease and other α-synucleinopathies are characterized by the deposition of intraneuronal α-synuclein (αSyn) inclusions. A significant fraction (about 15%) of αSyn in these pathological structures are truncated forms that have a much higher propensity than the full-length αSyn to form aggregates in vitro. However, little is known about the role of truncated αSyn species in pathogenesis or the means by which they are generated. Here, we have provided an in vitro mechanistic study demonstrating that truncated αSyns induce rapid aggregation of full-length protein at substoichiometric ratios. Co-overexpression of truncated αSyn with full-length protein increases cell vulnerability to oxidative stress in dopaminergic SH-SY5Y cells. These results suggest a precipitating role for truncated αSyn in the pathogenesis of diseases involving αSyn aggregation. In this regard, the A53T mutation found in some cases of familial Parkinson disease exacerbates the accumulation of insoluble αSyns that correlates with the onset of pathology in transgenic mice expressing human αSyn-A53T mutant. The caspase-like activity of the 20 S proteasome produces truncated fragments similar to those found in patients and animal models from degradation of unstructured αSyn. We propose a model in which incomplete degradation of αSyn, especially under overloaded proteasome capacity, produces highly amyloidogenic fragments that rapidly induce the aggregation of full-length protein. These aggregates in turn reduce proteasome activity, leading to further accumulation of fragmented and full-length αSyns, creating a vicious cycle of cytotoxicity. This model has parallels in other neurodegenerative diseases, such as Huntington disease, where coaggregation of poly(Q) fragments with full-length protein has been observed.
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U2 - 10.1074/jbc.M501508200
DO - 10.1074/jbc.M501508200
M3 - Article
C2 - 15840579
AN - SCOPUS:20744442130
SN - 0021-9258
VL - 280
SP - 22670
EP - 22678
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 24
ER -