Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates

Abstract

Insulin-like growth factor 2 (IGF2) protects against Huntington´s disease through the extracellular disposal of protein aggregates.

Insulin-Like Growth Factor 2 As a Possible Neuroprotective Agent and Memory Enhancer—Its Comparative Expression, Processing and Signaling in Mammalian CNS

“…Instead, IGF2 treatment enhanced the nonconventional disposal of soluble polyglutamine peptide species into the extracellular space through the secretion via microvesicles and exosomes. Knockdown of IGF2R decreased almost in half the levels of polyQ79-EGFP secretion, whereas the knockdown of IR or IGF1R did not have any effect on this [49]. Similar results were obtained in a study using a genetic model of AD: in the primary hippocampal cultures from Tg2576 mice overexpressing amyloid-β-precursor protein (APP), transduction with an IGF-2expressing vector caused a significant reduction of the extracellular Aβ42 level measured in the culture medium.…”

“…If we arranged all possible receptors by IGF-2 affinity to them, the list would most likely look like this: IGF1R > IGF2R = IR-A = IGF1R / IR-A heterodimer > IR-B = IGF1R / IR-B heterodimer [163]. However, some sources [15,49,156] imply that IGF-2 affinity to IGF2R is higher than to IGF1R.…”

“…Despite the fact that a number of reviews about IGF-2 and specifically about the IGF-2 function in the CNS have been published to date, some important aspects are not thoroughly discussed in many of these reviews, leading to conflicting statements. For example, there is a discrepancy between different papers about the primary source of IGF-2 in the adult organism: while some authors claim that IGF-2 is mainly synthesized in the brain [49,50], others name the liver as the organ producing most of IGF-2 [51][52][53].…”

Mastering organismal aging through the endoplasmic reticulum proteostasis network

“…Interestingly a recent report directly implicated the activity of IRE1α/RIDD in the downstream modulation of the DNA damage response affecting DNA repair and cell cycle control (Dufey et al, 2020), a pathway that has been extensively connected with the process of senescence. In addition, genetic targeting of XBP1 in the mouse brain was recently shown to trigger protective compesatory events resulting in the upregulation of IGF2, improving proteostasis in models of Huntington's disease (García‐Huerta et al, 2020). Because many small molecules (Hetz et al, 2019) and gene therapy approaches (Valenzuela et al, 2018) are under development to tune the ER proteostasis network in a disease context, interesting opportunities may become available in the near future to target the UPR in the context of aging, which promise an interesting holistic approach to prevent or attenuate the emergence of a variety of age‐related diseases affecting the human population.…”

On the Right Track to Treat Movement Disorders: Promising Therapeutic Approaches for Parkinson’s and Huntington’s Disease

“…In a recently published study, it has been demonstrated that the AAV administration of IGF2 into the striatum of YAC128 and R6/2 mice decreased the levels of mHTT and increased the levels of DARPP-32, a marker used to assess striatal neurons survival (García-Huerta et al, 2020 ). Interestingly, neuroprotective effects of IGF2 treatment have been described in preclinical models of others neurodegenerative diseases such as amyotrophic lateral sclerosis (Allodi et al, 2016 ), spinal muscular atrophy (Brown et al, 2009 ) and Alzheimer’s disease (Pascual-Lucas et al, 2014 ).…”