Familial Parkinson Disease-associated Mutations Alter the Site-specific Microenvironment and Dynamics of α-Synuclein

Abstract

Background: Aggregation of ␣-Syn is associated with PD pathogenesis. Results: Despite being natively unfolded, a site-specific structure exists in ␣-Syn that is significantly altered by familial PD-associated E46K, A53T, and A30P mutations. Conclusion: Altered site-specific structure of the PD-associated mutants may attribute to their different aggregation propensity. Significance: This study contributes to understanding the relationship between structure and aggregation of ␣-Syn.

Structure, function and toxicity of alpha‐synuclein: the Bermuda triangle in synucleinopathies

“…Subtle conformational alterations in the vicinity of the mutated residue might disturb the general native flexibility of the protein (Sahay et al . ). As discussed above, long‐range electrostatic interactions exist between the N‐ and C‐termini, and it is likely that these mutations, by altering these contacts, affect the stability of the native α‐syn disordered state (Bertoncini et al .…”

“…Thus, aberrant internal contacts may promote a partially folded intermediate that would increase the self‐assembly propensity (Sahay et al . ).…”

α-synuclein dimer structures found from computational simulations

“…This region also contains several residues (A30, E46, H50 G51 and A53) whose mutations (A30P, E46K, H50Q, G51D, A53T) alter the aggregation process [16][17][18][19][20][21][22][23] and are linked to familial forms of Parkinson's disease [24,25]. The central region, consisting of residues 61-95, is highly hydrophobic [26,27]. It is thought to be the core region for aggregation, mediated by its hydrophobicity [26].…”

“…The central region, consisting of residues 61-95, is highly hydrophobic [26,27]. It is thought to be the core region for aggregation, mediated by its hydrophobicity [26]. Finally, the C-terminal region, residues 96-140, is highly acidic and negatively charged.…”

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

“…Although α-syn was first discovered in patients with familial forms of PD and its A53T, E46K and A30P mutations had also been shown to be related to the familial form of PD [4,86], α-syn appeared to be a vital genetic factor of PD pathology both in familial and sporadic cases. Its expression level was positively correlated with the severity of PD [87].…”