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Defects in optineurin- and myosin VI-mediated cellular trafficking in amyotrophic lateral sclerosis

التفاصيل البيبلوغرافية
العنوان:	Defects in optineurin- and myosin VI-mediated cellular trafficking in amyotrophic lateral sclerosis
المؤلفون:	Vanessa Tan, Gilles J. Guillemin, Emily P. McCann, Jennifer A. Fifita, Manal A. Farg, Vinod Sundaramoorthy, Kelly L. Williams, Ian P. Blair, Julie D. Atkin, Adam K. Walker
المصدر:	Human molecular genetics. 26(17)
سنة النشر:	2017
مصطلحات موضوعية:	0301 basic medicine, Autophagosome, medicine.medical_specialty, Immunoprecipitation, Mutation, Missense, Cell Cycle Proteins, Biology, 03 medical and health sciences, symbols.namesake, Mice, Molecular genetics, Lysosome, Transcription Factor TFIIIA, Myosin, Genetics, medicine, Animals, Humans, Amyotrophic lateral sclerosis, Eye Proteins, Molecular Biology, Actin, Genetics (clinical), Cells, Cultured, Optineurin, Motor Neurons, Myosin Heavy Chains, Endoplasmic reticulum, Autophagy, Amyotrophic Lateral Sclerosis, Membrane Transport Proteins, General Medicine, Anatomy, Golgi apparatus, medicine.disease, Endoplasmic Reticulum Stress, Molecular biology, Cell biology, Blot, Protein Transport, 030104 developmental biology, medicine.anatomical_structure, Spinal Cord, biology.protein, Unfolded protein response, symbols, Antibody, Protein Binding
الوصف:	Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder primarily affecting motor neurons. Mutations in optineurin cause a small proportion of familial ALS cases, and wild-type (WT) optineurin is misfolded and forms inclusions in sporadic ALS patient motor neurons. However, it is unknown how optineurin mutation or misfolding leads to ALS. Optineurin acts an adaptor protein connecting the molecular motor myosin VI to secretory vesicles and autophagosomes. Here, we demonstrate that ALS-linked mutations p.Q398X and p.E478G disrupt the association of optineurin with myosin VI, leading to an abnormal diffuse cytoplasmic distribution, inhibition of secretory protein trafficking, endoplasmic reticulum (ER) stress and Golgi fragmentation in motor neuron-like NSC-34 cells. We also provide further insight into the role of optineurin as an autophagy receptor. WT optineurin associated with lysosomes and promoted autophagosome fusion to lysosomes in neuronal cells, implying that it mediates trafficking of lysosomes during autophagy in association with myosin VI. However, either expression of ALS mutant optineurin or small interfering RNA-mediated knockdown of endogenous optineurin blocked lysosome fusion to autophagosomes, resulting in autophagosome accumulation. Together these results indicate that ALS-linked mutations in optineurin disrupt myosin VI-mediated intracellular trafficking processes. In addition, in control human patient tissues, optineurin displayed its normal vesicular localization, but in sporadic ALS patient tissues, vesicles were present in a significantly decreased proportion of motor neurons. Optineurin binding to myosin VI was also decreased in tissue lysates from sporadic ALS spinal cords. This study therefore links several previously described pathological mechanisms in ALS, including defects in autophagy, fragmentation of the Golgi and induction of ER stress, to disruption of optineurin function. These findings also indicate that optineurin-myosin VI dysfunction is a common feature of both sporadic and familial ALS.
تدمد:	1460-2083
الوصول الحر:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fde00470b743d3612a18922da4e43ae1Test https://pubmed.ncbi.nlm.nih.gov/25859013Test
حقوق:	OPEN
رقم الانضمام:	edsair.doi.dedup.....fde00470b743d3612a18922da4e43ae1
قاعدة البيانات:	OpenAIRE

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Mutations in optineurin cause a small proportion of familial ALS cases, and wild-type (WT) optineurin is misfolded and forms inclusions in sporadic ALS patient motor neurons. However, it is unknown how optineurin mutation or misfolding leads to ALS. Optineurin acts an adaptor protein connecting the molecular motor myosin VI to secretory vesicles and autophagosomes. Here, we demonstrate that ALS-linked mutations p.Q398X and p.E478G disrupt the association of optineurin with myosin VI, leading to an abnormal diffuse cytoplasmic distribution, inhibition of secretory protein trafficking, endoplasmic reticulum (ER) stress and Golgi fragmentation in motor neuron-like NSC-34 cells. We also provide further insight into the role of optineurin as an autophagy receptor. WT optineurin associated with lysosomes and promoted autophagosome fusion to lysosomes in neuronal cells, implying that it mediates trafficking of lysosomes during autophagy in association with myosin VI. However, either expression of ALS mutant optineurin or small interfering RNA-mediated knockdown of endogenous optineurin blocked lysosome fusion to autophagosomes, resulting in autophagosome accumulation. Together these results indicate that ALS-linked mutations in optineurin disrupt myosin VI-mediated intracellular trafficking processes. In addition, in control human patient tissues, optineurin displayed its normal vesicular localization, but in sporadic ALS patient tissues, vesicles were present in a significantly decreased proportion of motor neurons. Optineurin binding to myosin VI was also decreased in tissue lysates from sporadic ALS spinal cords. This study therefore links several previously described pathological mechanisms in ALS, including defects in autophagy, fragmentation of the Golgi and induction of ER stress, to disruption of optineurin function. 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