IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease

Abstract

Aging is a major risk factor for the progression of neurodegenerative diseases, including Huntington disease (HD). Reduced neuronal IGF1 or Irs2 signaling have been shown to extend life span in mice. To determine whether Irs2 signaling modulates neurodegeneration in HD, we genetically modulated Irs2 concentrations in the R6/2 mouse model of HD. Increasing Irs2 levels in the brains of R6/2 mice significantly reduced life span and increased neuronal oxidative stress and mitochondrial dysfunction. In contrast, reducing Irs2 levels throughout the body (except in β cells, where Irs2 expression is needed to prevent diabetes onset; R6/2•Irs2 +/-•Irs2 βtg mice) improved motor performance and extended life span. The slower progression of HD-like symptoms was associated with increased nuclear localization of the transcription factor FoxO1 and increased expression of FoxO1-dependent genes that promote autophagy, mitochondrial function, and resistance to oxidative stress. Mitochondrial function improved and the number of autophagosomes increased in R6/2•Irs2 +/-•Irs2 βtg mice, whereas aggregate formation and oxidative stress decreased. Thus, our study suggests that Irs2 signaling can modulate HD progression. Since we found the expression of Irs2 to be normal in grade II HD patients, our results suggest that decreasing IRS2 signaling could be part of a therapeutic approach to slow the progression of HD.

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

“…Another study demonstrated that p-(Ser473)Akt was unchanged in YAC128 and in R6/2 HD mice, but the levels of p-(Ser421)Htt were decreased in the striatum of YAC128 mice and in cells expressing mHtt [79]. In contrast, insulin receptor substrate (IRS)-2, which activates PI-3K/Akt and mTOR cascade, promoted mitochondrial dysfunction and oxidative stress in R6/2 mice; however, in the same study, the authors showed that IRS-2 protein levels were unchanged in the striatum of patients with grade II HD [80]. Conversely, IRS-2 activation induced by insulin, IGF-1 and interleukin-4 enhanced exon1Htt clearance in a dosedependent manner [81].…”

Insulin receptor substrate signaling suppresses neonatal autophagy in the heart

“…Irs2 -/-mice exhibit peripheral insulin resistance and progress toward type 2 diabetes because of pancreatic β cell failure. Furthermore, decreased IRS2 protein levels resulted in increased autophagy in the brain and attenuated the progress of Huntington's disease in a transgenic mouse model by decreasing the number of protein aggregates (30). Together, these studies suggest a predominant role for IRS1 in the regulation of somatic growth and for IRS2 in the regulation of metabolism (26)(27)(28)(29).…”

Mitochondrial quality-control dysregulation in conditional HO-1–/– mice

“…Oxidative mitochondrial damage in cardiac I/R injury has been implicated as a cause of cell death (66), but the prevention of heme accumulation and nonfunctional protein aggregates that lead to a cycle of oxidative stress and deterioration of mitochondrial function is clearly protective (67). There is further evidence that energy depletion together with ROS and protein aggregation induces autophagy (68,69).…”