PERK inhibition delays neurodegeneration and improves motor function in a mouse model of Marinesco-Sjögren syndrome
Autor: | Liliana Comerio, Vanessa Capone, Valentina Grande, Michele Sallese, Francesca Ornaghi, Jeffrey M. Axten, Fabio Fiordaliso, Roberto Chiesa, Nicholas J. Laping, Daniele Tolomeo, Alessandro Corbelli, Antonio Masone, Elena Restelli |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Heterozygote Protein Folding Cerebellum Indoles Marinesco–Sjögren syndrome Purkinje cell Motor Activity Biology Endoplasmic Reticulum Mice Purkinje Cells eIF-2 Kinase 03 medical and health sciences 0302 clinical medicine Loss of Function Mutation Genetics medicine Animals Guanine Nucleotide Exchange Factors Humans HSP70 Heat-Shock Proteins Myopathy Molecular Biology Genetics (clinical) Spinocerebellar Degenerations Cerebellar ataxia Adenine Neurodegeneration General Medicine medicine.disease Disease Models Animal 030104 developmental biology medicine.anatomical_structure Nerve Degeneration Unfolded Protein Response Unfolded protein response Cancer research medicine.symptom Translational attenuation 030217 neurology & neurosurgery |
Zdroj: | Human Molecular Genetics. 27:2477-2489 |
ISSN: | 1460-2083 0964-6906 |
DOI: | 10.1093/hmg/ddy152 |
Popis: | Marinesco-Sjögren syndrome (MSS) is a rare, early onset, autosomal recessive multisystem disorder characterized by cerebellar ataxia, cataracts and myopathy. Most MSS cases are caused by loss-of-function mutations in the gene encoding SIL1, a nucleotide exchange factor for the molecular chaperone BiP which is essential for correct protein folding in the endoplasmic reticulum. Woozy mice carrying a spontaneous Sil1 mutation recapitulate key pathological features of MSS, including cerebellar atrophy with degeneration of Purkinje cells and progressive myopathy. Because the PERK branch of the unfolded protein response is activated in degenerating neurons of woozy mice, and inhibiting PERK-mediated translational attenuation has shown protective effects in protein-misfolding neurodegenerative disease models, we tested the therapeutic efficacy of GSK2606414, a potent inhibitor of PERK. Mice were chronically treated with GSK2606414 starting from a presymptomatic stage, and the effects were evaluated on biochemical, histopathological and clinical readouts. GSK2606414 delayed Purkinje cell degeneration and the onset of motor deficits, prolonging the asymptomatic phase of the disease; it also reduced the skeletal muscle abnormalities and improved motor performance during the symptomatic phase. The protein but not the mRNA level of ORP150, a nucleotide exchange factor which can substitute for SIL1, was increased in the cerebellum of GSK2606414-treated woozy mice, suggesting that translational recovery promoted the synthesis of this alternative BiP co-factor. Targeting PERK signaling may have beneficial disease-modifying effects in carriers of SIL1 mutations. |
Databáze: | OpenAIRE |
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