Activation of IGF-1 and Insulin Signaling Pathways Ameliorate Mitochondrial Function and Energy Metabolism in Huntington’s Disease Human Lymphoblasts

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Mitochondrial dysfunction associated with energy failure plays an important role in this untreated pathology. In the present work, we used lymphoblasts obtained from HD patients or unaffected parentally related individuals to study the protective role of insulin-like growth factor 1 (IGF-1) versus insulin (at low nM) on signaling and metabolic and mitochondrial functions. Deregulation of intracellular signaling pathways linked to activation of insulin and IGF-1 receptors (IR,IGF-1R), Akt, and ERK was largely restored by IGF-1 and, at a less extent, by insulin in HD human lymphoblasts. Importantly, both neurotrophic factors stimulated huntingtin phosphorylation at Ser421 in HD cells. IGF-1 and insulin also rescued energy levels in HD peripheral cells, as evaluated by increased ATP and phosphocreatine, and decreased lactate levels. Moreover, IGF-1 effectively ameliorated O2 consumption and mitochondrial membrane potential (Δψm) in HD lymphoblasts, which occurred concomitantly with increased levels of cytochrome c. Indeed, constitutive phosphorylation of huntingtin was able to restore the Δψm in lymphoblasts expressing an abnormal expansion of polyglutamines. HD lymphoblasts further exhibited increased intracellular Ca(2+) levels before and after exposure to hydrogen peroxide (H2O2), and decreased mitochondrial Ca(2+) accumulation, being the later recovered by IGF-1 and insulin in HD lymphoblasts pre-exposed to H2O2. In summary, the data support an important role for IR/IGF-1R mediated activation of signaling pathways and improved mitochondrial and metabolic function in HD human lymphoblasts.

Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells

“…A reduction in Tfam levels in brain lysates from HD patients was previously found [95]. We showed decreased Tfam levels in HD lymphoblasts [84] x Insulin/IGF-1 precludes mHtt-induced mitochondrial ROS formation and SOD activity.…”

Palmitate-induced Endoplasmic Reticulum stress and subsequent C/EBPα Homologous Protein activation attenuates leptin and Insulin-like growth factor 1 expression in the brain

“…This may have implications in understanding cellular mechanisms underlying neurodegenerative diseases. Indeed, dysregulation of leptin and IGF1 signaling is suggested to be implicated in AD [49, 50], Parkinson’s disease (PD) [51-55] and Huntington’s disease (HD) [56-59]. Multiple studies have established leptin as a promising target in the quest for therapeutic interventions in AD [9, 49].…”

Overexpression of BDNF and Full-Length TrkB Receptor Ameliorate Striatal Neural Survival in Huntington's Disease

“…We recently observed that phosphorylation of Htt (at Ser421) and AKT was related to improved brain metabolism of YAC128 mice subjected to intranasal administration of IGF-1 [40] and to improved mitochondrial function of HD human lymphoblasts treated with IGF-1 [41]. Moreover, increased levels of AKT and phosphorylated AKT in mitochondria were linked to enhanced mitochondrial function and decreased levels of mitochondrial reactive oxygen species in HD striatal cells [42].…”