Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway

Abstract

Conditional mouse models of polyglutamine diseases, such as Huntington's disease (HD), have revealed that cells can clear accumulated pathogenic proteins if the continuous production of the mutant transgene is halted. Invariably, the clearance of the protein leads to regression of the disease symptoms in mice. In light of these findings, it is critical to determine the pathway responsible for alleviating this protein accumulation to define targets to fight these diseases. In a functional genetic screen of HD, we found that activation of insulin receptor substrate-2, which mediates the signaling cascades of insulin and insulin-like growth factor 1, leads to a macroautophagy-mediated clearance of the accumulated proteins. The macroautophagy is triggered despite activation of Akt, mammalian target of rapamycin (mTOR), and S6 kinase, but still requires proteins previously implicated in macroautophagy, such as Beclin1 and hVps34. These findings indicate that the accumulation of mutant protein can lead to mTOR-independent macroautophagy and that lysosome-mediated degradation of accumulated protein differs from degradation under conditions of starvation.

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

“…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]. Thus, different IRS signaling pathways might be activated upon exposure to low nM insulin or IGF-1.…”

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

“…A reduction of levels of Beclin1 leads to the accumulation of mHtt and reduced the viability of animals in a mouse model of HD 156 . The autophagic response initiated by the exposure of cultured cells to Aß is mediated by PI3K 157 , and a similar induction of autophagy through PI3K occurs in cell culture models of HD 158 . On the other hand, blocking autophagy through the pharmacological inhibition of PI3K by 3-methyladenine increases the levels of mHtt and reduces viability 159 .…”

“…Reduced BDNF levels 39,40 Increasing BDNF & NGF levels is beneficial in disease models [51][52][53][54] Increased p75 NTR levels and signalling 75,172 Decreased Trk receptor levels and signalling 75,172 Increased Gsk3ß activity 66,173 Altered ERK activity 174 Reduced velocity and efficiency of axonal transport of BDNF 65,66 Apoptotic pathways Increased caspase-6 activity 89,90 Caspase-6 cleavage of disease proteins [89][90][91][92] Preventing caspase cleavage of disease proteins is beneficial in mouse models 93,94 Posttranslational modifications Palmitoylation of disease proteins is linked to aggregate formation 118,119 Phosphorylation of disease proteins reduces their cleavage by caspases 105,106 HDAC inhibition is beneficial in disease models 69,126,127 Protein aggregation and clearance mechanisms Misfolding and aggregation of disease proteins 128 UPS impairment 144,145 Impaired autophagy 161 Upregulation of autophagy is beneficial in disease models 153,155,156,158,162,163,165,167,<...>…”

Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and Bcl2A1 as critical target genes

“…The combined use of GEP and RNAi technology has been demonstrated to be a valuable strategy to validate potential drug targets (33)(34)(35), and RNAi has been recently used to efficiently probe the gene function on a whole-genome scale in mammalian cells (36,37). Here, ALK transcriptional targets were validated through a small-scale genetic screening, using lentiviral shRNA sequences.…”