Incretin mimetics restore the ER-mitochondrial axis and switch neuronal
fate towards survival.
Abstract
Background and Purpose: Amyotrophic lateral sclerosis with associated
frontotemporal dementia, Alzheimer’s disease, Huntington’s disease, and
Parkinson’s disease are the major neurodegenerative disorders that
afflict more than 7 million people worldwide. There are no
disease-modifying or disease-retarding therapeutic agents currently
available on the market. All four conditions feature several
seemingly-disparate pathological and genetic lesions, which, however,
converge into calcium dyshomeostasis and a disturbed function of the
axis of the endoplasmic reticulum (ER) and mitochondria. Experimental
Approach: Incretin mimetics – traditionally anti-diabetic therapeutic
agents – have been repeatedly shown to exert neurotrophic effects in
neuroblastoma cells, rodent primary neurones, and murine models of
neurodegeneration. Herein, for the very first time, we assess the
pharmacological effects of Liraglutide and the dual incretin DA-CH3 in
terminally differentiated human neurones under conditions of
calcium-dependent chronic ER stress and additionally assess their
efficacy in one of the most critical regulatory point for neurones, the
mitochondrial respiration and dynamics. Key Results: Liraglutide and
DA-CH3 rescue the arrested oxidative phosphorylation and glycolysis.
They mitigate the suppressed mitochondrial biogenesis and
hyper-polarisation of the mitochondrial membrane, all, to re-establish
normalcy of cellular bioenergetics under conditions of chronic ER
stress. These effects correlate with a resolution of the unfolded
protein response and the autophagic arrest to halt the excessive
synaptic and neuronal death, with the dual incretin displaying a
superior anti-apoptotic effect. Conclusions: Our findings pave the way
for a therapeutic strategy for disorders with a considerable
social-economic burden and deepen our understanding of the spectrum of
the incretin-signalling functions.