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Tytuł pozycji:

Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment

Tytuł:
Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment
Autorzy:
Pascal Laforêt
Michio Inoue
Evelyne Goillot
Claire Lefeuvre
Umut Cagin
Nathalie Streichenberger
Sarah Leonard-Louis
Guy Brochier
Angeline Madelaine
Clemence Labasse
Carola Hedberg-Oldfors
Thomas Krag
Louisa Jauze
Julien Fabregue
Philippe Labrune
Jose Milisenda
Aleksandra Nadaj-Pakleza
Sabrina Sacconi
Federico Mingozzi
Giuseppe Ronzitti
François Petit
Benedikt Schoser
Anders Oldfors
John Vissing
Norma B. Romero
Ichizo Nishino
Edoardo Malfatti
Temat:
Glycogen storage disease III
Muscle glycogenosis
Metabolic myopathies
Myopathology
Autophagy
Autophagic impairment
Neurology. Diseases of the nervous system
RC346-429
Źródło:
Acta Neuropathologica Communications, Vol 7, Iss 1, Pp 1-16 (2019)
Wydawca:
BMC, 2019.
Rok publikacji:
2019
Kolekcja:
LCC:Neurology. Diseases of the nervous system
Typ dokumentu:
article
Opis pliku:
electronic resource
Język:
English
ISSN:
2051-5960
Relacje:
http://link.springer.com/article/10.1186/s40478-019-0815-2; https://doaj.org/toc/2051-5960
DOI:
10.1186/s40478-019-0815-2
Dostęp URL:
https://doaj.org/article/93fd2c97c0914ab89cce0bad8ec56750  Link otwiera się w nowym oknie
Numer akcesji:
edsdoj.93fd2c97c0914ab89cce0bad8ec56750
Czasopismo naukowe
Abstract Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene. In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model. In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples. These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.
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