Septin regulation of Orai-mediated Ca²⁺ entry - a novel target for neurodegeneration

Area of Science:

• Neuroscience
• Cell Biology
• Pharmacology

Background:

• Aberrant calcium (Ca2+) signaling is a key feature in neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD).
• Developing therapies to specifically target harmful Ca2+ signals without disrupting normal neuronal function remains a significant challenge.

Purpose of the Study:

• To identify drugs that can specifically reduce excessive Ca2+ entry in a cellular model of AD.
• To investigate the role of Septins in regulating Ca2+ signaling and their potential as therapeutic targets.

Main Methods:

• A drug screen was performed using the tauP301L cell model of AD to find compounds ameliorating excess Ca2+ entry.
• The identified compounds (ReS19-T) were tested in cellular, mouse, and human iPSC-derived neuron models.
• Septin filament architecture was analyzed in disease conditions with and without drug treatment.

Main Results:

• A class of compounds, ReS19-T, interacting with Septins, was identified.
• Treatment with ReS19-T alleviated cellular and systemic deficits in tauP301L models.
• Abnormal Septin filament architecture was linked to aberrant endoplasmic reticulum-plasma membrane (ER-PM) contacts, causing excess Ca2+ entry.

Conclusions:

• Septins play a crucial role in organizing ER-PM junctions to regulate Ca2+ entry through Orai channels.
• Targeting Septins with ReS19-T represents a promising therapeutic strategy for neurodegenerative diseases characterized by aberrant Ca2+ signaling.