Multifaceted interactions mediated by intrinsically disordered regions play key roles in alpha synuclein aggregation

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Alpha Synuclein (α-Syn) aggregation into fibrils is a hallmark of neurodegenerative diseases like Parkinson's.
• Pathologic α-Syn aggregates exhibit diverse fibril structures and spread between cells through templated seeding.
• Monomeric α-Syn is an intrinsically disordered protein (IDP) with distinct terminal domains.

Purpose of the Study:

• To review recent findings on the mechanism of α-Syn aggregation.
• To identify the roles of the N- and C-terminal domains in α-Syn aggregation and propagation.
• To explore novel therapeutic strategies for synucleinopathies.

Main Methods:

• Literature review of recent research on α-Syn aggregation mechanisms.
• Analysis of the structural and functional roles of α-Syn's intrinsically disordered terminal domains.
• Investigation of the impact of C-terminal charge content on fibril growth and templated seeding.

Main Results:

• The N- and C-terminal domains play critical, multifaceted roles in initiating and growing α-Syn aggregates.
• Templated seeding, crucial for cell-to-cell propagation, is influenced by these terminal domains.
• The C-terminal domain's charge, sensitive to pH, modulates intermolecular interactions in fibril growth and propagation.

Conclusions:

• Understanding the complex roles of α-Syn's terminal domains provides insights into disease pathogenesis.
• These domains represent promising targets for developing inhibitors against synucleinopathies.
• Targeting α-Syn aggregation and propagation offers a potential therapeutic avenue for neurodegenerative diseases.