TY - JOUR
T1 - Activation of autophagy attenuates motor deficits and extends lifespan in a C. elegans model of ALS
AU - Xu, Hui
AU - Jia, Congcong
AU - Cheng, Cheng
AU - Wu, Haifeng
AU - Cai, Huaibin
AU - Le, Weidong
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (NSFC 81771521 and 31700853 ), the Guangdong Provincial Key R & D Program ( 2018B030337001 ), and in part by the Intramural Research Programs of National Institute on Aging, NIH ( HC, ZIA AG000944 , AG000928 ). Strains used in this work were provided by the Caenorhabditis Genetics Center ( CGC ), which is funded by NIH Office of Research Infrastructure Programs ( P40 OD010440 ).
Funding Information:
Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disease [1]. Most ALS cases occur sporadically, while approximately 10% are familial [2]. One of the most prevalent familial forms of the disease involves mutations of Cu/Zn?superoxide dismutase 1 (SOD1) [3]. Since the discovery of SOD1 G93A missense mutation in 1993 [4], more than 185 different ALS-related SOD1 mutations have been identified [3]. The disease causal effect of SOD1 mutations is attributed to the degeneration of motor neurons [5]. Despite decades of research, the pathogenesis of ALS and the mechanism by which SOD1 mediates its toxic effects in motor neurons are not fully understood. Studies on neuronal dysfunction have primarily relied on models overexpressing human SOD1 protein and have supported a role for SOD1 dysfunction in ALS pathogenesis [6]. However, these findings have limited translational value in terms of extending the lifespan of ALS patients and the development of effective therapeutics. Although the degeneration of motor neurons in ALS is mainly attributable to the missense mutation in SOD1 and aggregation of SOD1 protein, the specific molecular events and pathways involved have yet to be fully elucidated. As such, there is a need for a more suitable model to investigate the etiopathogenesis of ALS and evaluate the efficacy of potential drugs for its treatment. Although the clinical course is variable, ALS patients generally have short lifespan. The molecular basis for short lifespan and whether it is mediated by pathways known to regulate longevity are open questions. It was reported that a prolonged lifespan depends on the FOXO transcription factor DAF-16 [7] and may be related to autophagy and various aspects of cellular and organismal aging. Furthermore, autophagy has been directly linked to neurodegeneration and ageing by an extensive body of research [8]. However, our understanding of the mechanistic link between autophagy and lifespan is limited, particularly with regard to neurodegenerative diseases.Transgenic Caenorhabditis elegans (C. elegans) models have been established for a number of neurodegenerative diseases, such as Alzheimer's disease (AD) [16], Parkinson's disease (PD) [17], and ALS [18]. It is also a useful tool for evaluating the toxicity of mutant SOD1 in motor neurons and for exploring the mechanisms by which SOD1 mutation affects longevity and other physiologic functions in ALS. SOD1 overexpression models support a role for SOD1-mediated toxicity in the pathogenesis of ALS [19]. In our previous work, we found that hSOD1 aggregates and forms inclusions in the motor neurons of C. elegans [20]. The hSOD1-induced death of motor neurons is independent of the Cell death protein 4 (CED-4)/CED-3 apoptosis pathway [20]. Recent studies in ALS models have demonstrated that mutant SOD1 not only induces toxicity in motor neurons but also reduces longevity, possibly due to mutant SOD1 aggregation [21,22]. Verapamil was shown to inhibit the aggregation of mutant SOD1, promote motor neuron survival, and extend lifespan in SOD1G93A mice by inducing the activation of autophagy [23]; meanwhile, shatavarin IV prevented reactive oxygen species-induced oxidative damage in C. elegans and prolonged lifespan by downregulating the expression of the Leucine-rich repeats, Ras-like domain, kinase 1 (lrk-1) gene [24]. These findings provide evidences that mutant SOD1 causes motor neuron damage and short lifespan through complex mechanisms. However, the specific mechanisms underlying these effects remain unknown.This work was supported by the National Natural Science Foundation of China (NSFC 81771521 and 31700853), the Guangdong Provincial Key R & D Program (2018B030337001), and in part by the Intramural Research Programs of National Institute on Aging, NIH (HC, ZIA AG000944, AG000928). Strains used in this work were provided by the Caenorhabditis Genetics Center (CGC), which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
Publisher Copyright:
© 2022
PY - 2022/3
Y1 - 2022/3
N2 - Mutations in Cu/Zn–superoxide dismutase 1 (SOD1) are linked to amyotrophic lateral sclerosis (ALS). Using a line of ALS-related mutant human SOD1 (hSOD1) transgenic Caenorhabditis elegans, we determined the effects of metformin on the progression of ALS-like pathological abnormalities. We found that metformin significantly extended the lifespan, improved motor performance, and enhanced antioxidant activity of mutant worms. We further showed that metformin enhanced expression of lgg-1, daf-16, skn-1 and other genes known to regulate autophagy, longevity and oxidative stress in hSOD1 transgenic worms. Accordingly, overexpression of lgg-1 or daf-16 attenuated the aging and pathological abnormalities of mutant human SOD1 worms, while genetic deletion of lgg-1 or daf-16 abolished the beneficial effects of metformin. Collectively, we demonstrate that metformin protects against mutant SOD1-induced cytotoxicity in part through enhancement of autophagy and extends lifespan through daf-16 pathway. Our findings suggest that metformin could be further explored as a potential therapeutic agent in treating ALS.
AB - Mutations in Cu/Zn–superoxide dismutase 1 (SOD1) are linked to amyotrophic lateral sclerosis (ALS). Using a line of ALS-related mutant human SOD1 (hSOD1) transgenic Caenorhabditis elegans, we determined the effects of metformin on the progression of ALS-like pathological abnormalities. We found that metformin significantly extended the lifespan, improved motor performance, and enhanced antioxidant activity of mutant worms. We further showed that metformin enhanced expression of lgg-1, daf-16, skn-1 and other genes known to regulate autophagy, longevity and oxidative stress in hSOD1 transgenic worms. Accordingly, overexpression of lgg-1 or daf-16 attenuated the aging and pathological abnormalities of mutant human SOD1 worms, while genetic deletion of lgg-1 or daf-16 abolished the beneficial effects of metformin. Collectively, we demonstrate that metformin protects against mutant SOD1-induced cytotoxicity in part through enhancement of autophagy and extends lifespan through daf-16 pathway. Our findings suggest that metformin could be further explored as a potential therapeutic agent in treating ALS.
KW - ALS
KW - Autophagy
KW - Lifespan
KW - Metformin
KW - Neuroprotection
KW - Amyotrophic Lateral Sclerosis/drug therapy
KW - Mice, Transgenic
KW - Caenorhabditis elegans/metabolism
KW - Motor Neurons/metabolism
KW - Animals
KW - Longevity/genetics
KW - Superoxide Dismutase/metabolism
KW - Mice
KW - Disease Models, Animal
KW - Superoxide Dismutase-1/genetics
UR - http://www.scopus.com/inward/record.url?scp=85123919451&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123919451&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2022.01.030
DO - 10.1016/j.freeradbiomed.2022.01.030
M3 - Article
C2 - 35114355
AN - SCOPUS:85123919451
SN - 0891-5849
VL - 181
SP - 52
EP - 61
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -