The role of insulin-like growth factor 1 in ALS cell and mouse models: A mitochondrial protector

• Published in: Brain research bulletin Vol. 144; pp. 1 - 13
• Main Authors: Wen, Di, Cui, Can, Duan, Weisong, Wang, Wan, Wang, Ying, Liu, Yakun, Li, Zhongyao, Li, Chunyan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2019
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Apoptosis - physiology; Cell Line; Disease Models, Animal; Disease Progression; DNA-Binding Proteins - metabolism; Female; Humans; Insulin-like growth factor 1; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - physiology; Intrinsic apoptosis pathway; Male; Membrane Potential, Mitochondrial - physiology; Mice; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; Mitophagy; Mitophagy - physiology; Motor Neurons - metabolism; Neurodegenerative Diseases - metabolism; Peptide Fragments - metabolism; Superoxide Dismutase - metabolism; TDP-25; Transgenic SOD1G93A mice; Mitochondria; Amyotrophic lateral sclerosis; Intrinsic apoptosis pathway; TDP-25; Mitophagy; Insulin-like growth factor 1; Transgenic SOD1G93A mice; Transgenic SOD1(G93A) mice
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/j.brainresbull.2018.09.015

•ScAAV9-hIGF-1 increased Bcl-xl, Bcl-2, and decreased Bax, Bak in mitochondria.•ScAAV9-hIGF-1 reduced the mitochondrial cytochrome c release.•IGF-1 hyperpolarized the MMP, and the abnormal mitochondria were transformed.•The protective effect of IGF-1 on mitochondria decreased after genetic deletion.•IGF-1 altered the level of mitophagy markers (LC3-II, p62, optineurin). Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disorder, but little is known about the exact causes and pathophysiology of this disease. In transgenic mouse models of ALS, mitochondrial abnormalities develop during the disease and might contribute to the progression of ALS. Gene therapy was recently shown to induce beneficial effects. For example, the delivery of human insulin-like growth factor-1 (hIGF-1) by self-complementary adeno-associated virus (AAV) vectors has been shown to prolong the lifespan of ALS transgenic mice. However, the function of IGF-1 in mitochondria has not been systematically studied in ALS models. In this study, scAAV9-hIGF-1 was intramuscularly injected into transgenic SOD1G93A mice and administered to cell lines expressing the ∼25-kDa C-terminal fragment of transactive response DNA-binding protein (TDP-25). The mitochondrial electrical transmembrane potential was hyperpolarized, and electron microscopy findings revealed that the abnormal mitochondria were transformed. Moreover, the intrinsic mitochondrial apoptotic process was modified through the upregulation of anti-apoptotic proteins (B-cell lymphoma-extra large (Bcl-xl) and B-cell lymphoma-2 (Bcl-2)), the downregulation of pro-apoptotic proteins (Bcl-2-associated x protein (Bax) and Bcl-2 homologous antagonist killer (Bak)) and a reduction in mitochondrial cytochrome c release. Mitophagy was also increased after scAAV9-hIGF-1 treatment, as evidenced by a decrease in the p62 level and an increase in the LC3-II level. Furthermore, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) system was used to delete the IGF-1 gene in SOD1G93A model mice via an intrathecal injection of scAAV9-sgRNA-IGF1-Cas9 to confirm these findings. The protective effect of IGF-1 on the mitochondria decreased after genetic deletion. These novel findings demonstrate that IGF-1 strongly protects mitochondria from apoptosis and upregulates mitophagy in mouse and cell models of ALS. Therefore, therapies that specifically protect mitochondrial function might be promising strategies for treating ALS.