Respiratory pathology in the Optn mouse model of Amyotrophic Lateral Sclerosis

McCall, Angela L; Dhindsa, Justin; Pucci, Logan; Kahn, Amanda F; Fusco, Anna; Biswas, Debolina D.; Strickland, Laura M; Tseng, Henry; ElMallah, Mai K.

doi:10.1016/j.resp.2020.103525

Cited by 7 publications

(1 citation statement)

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“…Moreover, another report showed that loss of OPTN function contributes to the pathogenesis of recessive ALS through S174X mutations [11]. Loss of the functional OPTN protein disrupts necroptosis, autophagy, and inflammation, which are involved in the pathogenesis of ALS [12]. Dysfunction of the autophagy pathway, which leads to cytosolic protein aggregation in MNs, was found to be a key histopathological hallmark of ALS [10].…”

Section: Introductionmentioning

confidence: 99%

OPTN gene therapy increases autophagy and protects mitochondria in SOD1‐G93A‐expressing transgenic mice and cells

Wen,

Ji,

et al. 2023

The FEBS Journal

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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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Section: Introductionmentioning

confidence: 99%