Abstract
Aggregated a-synuclein is the major component of inclusions in Parkinson’s disease and other synucleinopathy brains indicating that a-syn aggregation is associated with the pathogenesis of neurodegenerative disorders. Although the mechanisms underlying a-syn aggregation and toxicity are not fully elucidated, it is clear that a-syn undergoes post-trasnlational modifications and interacts with numerous proteins and other macromolecules, metals, hormones, neurotransmitters, drugs and poisons that can all modulate its aggregation propensity. The current and most recent findings regarding the factors modulating a-syn aggregation process are discussed in detail.
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Notes
- 1.
In amyloid literature, the term “protofibril” can also be found describing elongated aggregates that follow oligomer formation and precede fibrils.
- 2.
CK1 phosphorylates α-syn at both S87 and S129.
- 3.
Hydrogen peroxide can oxidize the amino acids Met, Cys and Trp, but αsyn contains only Met.
- 4.
- 5.
Dynein is a motor protein that transports cellular cargos by “walking” along cytoskeletal microtubules towards the minus end of the microtubule.
- 6.
The neurotransmitter serotonin, which is not a catecholamine, has been recently shown to inhibit α-syn fibrillation, by stabilizing intermediate aggregates of α-syn forming SDS-resistant oligomers, which are partially structured, containing substantial levels of β-sheet conformation (Falsone et al. 2011). The interaction of α-syn-serotonin is mediated by the C-terminal region of α-syn, as serotonin did not inhibit the fibrillation of the C-terminally truncated α-syn (Falsone et al. 2011).
- 7.
Oxidative stress is due to the imbalance between the generation of reactive oxygen species (ROS) and the biological system’s ability to counteract the effect of these species and repair the resulting damage.
- 8.
From the greek “δενδρο” meaning tree or branch-like.
Abbreviations
- a-Syn:
-
a-Synuclein
- AD:
-
Alzheimer’s disease
- DLB:
-
Dementia with Lewy bodies
- MSA:
-
multiple system atrophy
- NAC:
-
Non-amyloid component
- PD:
-
Parkinson’s disease
- LBs:
-
Lewy bodies
- wt:
-
wild type
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Paleologou, K.E., El-Agnaf, O.M.A. (2012). α-Synuclein Aggregation and Modulating Factors. In: Harris, J. (eds) Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease. Subcellular Biochemistry, vol 65. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5416-4_6
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