N-Terminal Acetylation of alpha-Synuclein Slows down Its Aggregation Process and Alters the Morphology of the Resulting Aggregates
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N-Terminal Acetylation of alpha-Synuclein Slows down Its Aggregation Process and Alters the Morphology of the Resulting Aggregates. / Bell, Rosie; Thrush, Rebecca J.; Castellana-Cruz, Marta; Oeller, Marc; Staats, Roxine; Nene, Aishwarya; Flagmeier, Patrick; Xu, Catherine K.; Satapathy, Sandeep; Galvagnion, Celine; Wilson, Mark R.; Dobson, Christopher M.; Kumita, Janet R.; Vendruscolo, Michele.
In: Biochemistry, Vol. 61, No. 17, 2022, p. 1743–1756.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - N-Terminal Acetylation of alpha-Synuclein Slows down Its Aggregation Process and Alters the Morphology of the Resulting Aggregates
AU - Bell, Rosie
AU - Thrush, Rebecca J.
AU - Castellana-Cruz, Marta
AU - Oeller, Marc
AU - Staats, Roxine
AU - Nene, Aishwarya
AU - Flagmeier, Patrick
AU - Xu, Catherine K.
AU - Satapathy, Sandeep
AU - Galvagnion, Celine
AU - Wilson, Mark R.
AU - Dobson, Christopher M.
AU - Kumita, Janet R.
AU - Vendruscolo, Michele
PY - 2022
Y1 - 2022
N2 - Parkinson's disease is associated with the aberrant aggregation of alpha-synuclein. Although the causes of this process are still unclear, post-translational modifications of alpha-synuclein are likely to play a modulatory role. Since alpha-synuclein is constitutively N-terminally acetylated, we investigated how this post-translational modification alters the aggregation behavior of this protein. By applying a three-pronged aggregation kinetics approach, we observed that N-terminal acetylation results in a reduced rate of lipid-induced aggregation and slows down both elongation and fibrilcatalyzed aggregate proliferation. An analysis of the amyloid fibrils produced by the aggregation process revealed different morphologies for the acetylated and nonacetylated forms in both lipid-induced aggregation and seed-induced aggregation assays. In addition, we found that fibrils formed by acetylated alpha-synuclein exhibit a lower beta-sheet content. These findings indicate that N-terminal acetylation of alpha-synuclein alters its lipid-dependent aggregation behavior, reduces its rate of in vitro aggregation, and affects the structural properties of its fibrillar aggregates.
AB - Parkinson's disease is associated with the aberrant aggregation of alpha-synuclein. Although the causes of this process are still unclear, post-translational modifications of alpha-synuclein are likely to play a modulatory role. Since alpha-synuclein is constitutively N-terminally acetylated, we investigated how this post-translational modification alters the aggregation behavior of this protein. By applying a three-pronged aggregation kinetics approach, we observed that N-terminal acetylation results in a reduced rate of lipid-induced aggregation and slows down both elongation and fibrilcatalyzed aggregate proliferation. An analysis of the amyloid fibrils produced by the aggregation process revealed different morphologies for the acetylated and nonacetylated forms in both lipid-induced aggregation and seed-induced aggregation assays. In addition, we found that fibrils formed by acetylated alpha-synuclein exhibit a lower beta-sheet content. These findings indicate that N-terminal acetylation of alpha-synuclein alters its lipid-dependent aggregation behavior, reduces its rate of in vitro aggregation, and affects the structural properties of its fibrillar aggregates.
KW - DISEASE
KW - MUTATION
KW - PARKINSON
KW - TOXICITY
KW - GENETICS
KW - BINDING
KW - IMPACT
U2 - 10.1021/acs.biochem.2c00104
DO - 10.1021/acs.biochem.2c00104
M3 - Journal article
C2 - 35944093
VL - 61
SP - 1743
EP - 1756
JO - Biochemistry
JF - Biochemistry
SN - 0006-2960
IS - 17
ER -
ID: 318528026