Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca²⁺ and synaptic defects.

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are linked neurodegenerative diseases characterized by TAR DNA-binding protein-43 (TDP43) pathology.
• Disrupted signaling between the endoplasmic reticulum (ER) and mitochondria, mediated by VAPB-PTPIP51 tethers, is implicated in FTD/ALS pathogenesis.
• This disruption involves the activation of glycogen kinase-3β (GSK3β) in response to TDP43-related insults.

Purpose of the Study:

• To investigate whether enhancing ER-mitochondria signaling via VAPB-PTPIP51 tethers can correct TDP43-induced damage in FTD/ALS.
• To determine if ursodeoxycholic acid (UDCA) can ameliorate TDP43-linked damage to ER-mitochondria communication and its therapeutic potential.

Main Methods:

• Overexpression of VAPB or PTPIP51 to enhance ER-mitochondria signaling.
• Assessing the impact on inositol 1,4,5-trisphosphate (IP3) receptor-mediated Ca2+ delivery to mitochondria.
• Evaluating synaptic function and the effect of UDCA on VAPB-PTPIP51 interaction and GSK3β activation in TDP43 models.

Main Results:

• Overexpression of VAPB or PTPIP51 restored normal Ca2+ delivery to mitochondria and improved synaptic function, counteracting mutant TDP43-induced damage.
• Ursodeoxycholic acid (UDCA) was found to correct TDP43-associated damage to the VAPB-PTPIP51 interaction.
• UDCA's therapeutic effect was linked to the inhibition of TDP43-mediated GSK3β activation.

Conclusions:

• Enhancing ER-mitochondria signaling through VAPB-PTPIP51 tethers shows promise for treating FTD/ALS.
• UDCA demonstrates potential as a therapeutic agent for FTD/ALS by restoring ER-mitochondria communication and inhibiting GSK3β.
• Targeting VAPB-PTPIP51 tethers represents a potential therapeutic strategy for FTD/ALS and other age-related neurodegenerative diseases.