근위축성측삭경화증의 SOD1-G93A 유전자 이식 마우스모델에서 라파마이신의 신경보호효과
Neuroprotective Effect of Rapamycin (Autophagy Enhancer) in Transgenic SOD1-G93A Mice of Amyotrophic Lateral Sclerosis
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background: The autophagy is the major route for lysosomal degradation of misfolded protein aggregates and oxidative cell components. We hypothesized that rapamycin (autophagy enhancer) would prolong the survival of motor neuron and suppress the disease progression in amyotrophic lateral sclerosis (ALS). Methods: A total of 24 transgenic mice harboring the human G93A mutated SOD1 gene were used. The clinical status involving rotarod test and survival, and biochemical study of ALS mice model were evaluated. Results: The onset of symptoms was significantly delayed in the rapamycin administration group compared with the control group. However, after the clinical symptom developed, the rapamycin exacerbated the disease progression and shortened the survival of ALS mice model, and apoptosis signals were up-regulated compared with control group. Conclusions: Even though further detailed studies on the relevancy between autophagy and ALS will be needed, our results revealed that the rapamycin administration was not effective for being novel promising therapeutic strategy in ALS transgenic mice and exacerbated the apoptosis.
Abstract
Background: The autophagy is the major route for lysosomal degradation of misfolded protein aggregates and oxidative cell components. We hypothesized that rapamycin (autophagy enhancer) would prolong the survival of motor neuron and suppress the disease progression in amyotrophic lateral sclerosis (ALS). Methods: A total of 24 transgenic mice harboring the human G93A mutated SOD1 gene were used. The clinical status involving rotarod test and survival, and biochemical study of ALS mice model were evaluated. Results: The onset of symptoms was significantly delayed in the rapamycin administration group compared with the control group. However, after the clinical symptom developed,the rapamycin exacerbated the disease progression and shortened the survival of ALS mice model, and apoptosis signals were up-regulated compared with control group. Conclusions: Even though further detailed studies on the relevancy between autophagy and ALS will be needed, our results revealed that the rapamycin administration was not effective for being novel promising therapeutic strategy in ALS transgenic mice and exacerbated the apoptosis.
참고문헌 (17)
- Okado-Matsumoto A, "Amyotrophic lateral sclerosis: a proposed mechanism", Proc Natl Acad Sci USA 2002;, 99, pp.9010~9014 (2002)
- Wang Q, "Protein aggregation and protein instability govern familial amyotrophic lateral sclerosis patient survival", PLoS Biol, 6, pp.e170~ (2008)
- Sreedharan J, "TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis", Science, 319, pp.1668~1672 (2008)
- Fornai F, "Lithium delays progression of amyotrophic lateral sclerosis", Proc Natl Acad Sci USA, 105, pp.2052~2057 (2008)
- Pasquali L, "Autophagy, lithium, and amyotrophic lateral sclerosis", Muscle Nerve, 40, pp.173~194 (2009)
- Fornai F, "Autophagy and amyotrophic lateral sclerosis: The multiple roles of lithium", Autophagy, 4, pp.527~530 (2008)
- Ravikumar B, "Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease", Nat Genet, 36, pp.585~595 (2004)
- Erlich S, "Rapamycin is a neuroprotective treatment for traumatic brain injury", Neurobiol Dis, 26, pp.86~93 (2007)
- Sarkar S, "Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies", Cell Death Differ, 16, pp.46~56 (2009)
- Ravikumar B, "Rapamycin pre-treatment protects against apoptosis", Hum Mol Genet, 15, pp.1209~1216 (2006)
- Pan T, "The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease", Brain, 131, pp.1969~1978 (2008)
- Ventruti A, "Autophagy and neurodegeneration", Curr Neurol Neurosci Rep, 7, pp.443~451 (2007)
- Ling D, "A central role for autophagy in Alzheimertype neurodegeneration", Autophagy, 5, pp.738~740 (2009)
- Pan T, "Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement", Neurobiol Dis, 32, pp.16~25 (2008)
- Koh SH, "Inhibition of glycogen synthase kinase-3 suppresses the onset of symptoms and disease progression of G93A-SOD1 mouse model of ALS", Exp Neurol, 205, pp.336~346
- Harrison DE, "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice", Nature, 460, pp.392~395 (2009)
- Zhang X, "Rapamycin treatment augments motor neuron degeneration in SOD1 (G93A) mouse model of amyotrophic lateral sclerosis", Autophagy, 7, pp.412~425 (2011)