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OPTN gene therapy increases autophagy and protects mitochondria in SOD1-G93A-expressing transgenic mice and cells.
Wen, Di; Ji, Yingxiao; Li, Yuanyuan; Duan, Weisong; Wang, Yanyan; Li, Zhongyao; Tao, Meichun; Liu, Yakun.
Afiliación
  • Wen D; Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
  • Ji Y; Department of Neurology, Hebei General Hospital, Shijiazhuang, China.
  • Li Y; Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
  • Duan W; Neurological Laboratory of Hebei Province, Shijiazhuang, China.
  • Wang Y; Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
  • Li Z; Neurological Laboratory of Hebei Province, Shijiazhuang, China.
  • Tao M; Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
  • Liu Y; Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
FEBS J ; 291(4): 795-813, 2024 Feb.
Article en En | MEDLINE | ID: mdl-37983563
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron (MN) death. Mutation of the superoxide dismutase 1 (SOD1) gene, which results in abnormal protein aggregation, is one of the causes of familial ALS. Autophagic dysfunction occurs in SOD1-G93A mutant mice as the disease progresses, but the etiology of this disease is still unclear. Optineurin (OPTN) is an adaptor that is involved in autophagy and participates in aggrephagy and mitophagy. Previous studies have established that OPTN mutations contribute to diseases such as glaucoma and ALS. However, the function of OPTN in autophagy and mitophagy has not been intensively investigated in models of ALS. In this study, we assessed the beneficial effect of OPTN on autophagy and mitochondrial function by intrathecally injecting adeno-associated virus 9 (AAV9)-OPTN into SOD1-G93A transgenic mice and by administering lentivirus (LV)-OPTN to cells expressing the SOD1-G93A mutant protein. The expression of voltage-dependent anion channel 1 (VDAC1) was increased and autophagy was elevated after OPTN gene therapy, as shown by a lower level of p62 and a higher level of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II. Moreover, using electron microscopy, we observed a hyperpolarized mitochondrial transmembrane potential and reversal of mitochondrial morphological abnormalities. Furthermore, the protein level of TANK-binding kinase 1 (TBK1) was increased, suggesting that mitophagy was increased. Our findings from both animal and cell line studies strongly suggest that OPTN gene therapy is a powerful strategy to increase autophagy and protect mitochondria to prevent the progression of ALS and could be effective in the treatment of ALS.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esclerosis Amiotrófica Lateral Límite: Animals Idioma: En Revista: FEBS J Asunto de la revista: BIOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esclerosis Amiotrófica Lateral Límite: Animals Idioma: En Revista: FEBS J Asunto de la revista: BIOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido