Altered retinal structure and function in Spinocerebellar ataxia type 3
Por:
Toulis V, Casaroli-Marano R, Camós-Carreras A, Figueras-Roca M, Sánchez-Dalmau B, Muñoz E, Ashraf NS, Ferreira AF, Khan N, Marfany G and do Carmo Costa M
Publicada:
1 ago 2022
Ahead of Print:
1 may 2022
Categoría:
Neurology
Resumen:
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine (polyQ)-encoding CAG repeat in the ATXN3 gene. Because the ATXN3 protein regulates photoreceptor ciliogenesis and phagocytosis, we aimed to explore whether expanded polyQ ATXN3 impacts retinal function and integrity in SCA3 patients and transgenic mice.We evaluated the retinal structure and function in five patients with SCA3 and in a transgenic mouse model of this disease (YACMJD84.2, Q84) using optical coherence tomography (OCT) and electroretinogram (ERG). In the transgenic mice, we further: a) determined the retinal expression pattern of ATXN3 and the distribution of cones and rods using immunofluorescence (IF); and b) assessed the retinal ultrastructure using transmission electron microscopy (TEM).Some patients with SCA3 in our cohort revealed: i) reduced central macular thickness indirectly correlated with disease duration; ii) decreased thickness of the macula and the ganglion cell layer, and reduced macula volume inversely correlated with disease severity (SARA score); and iii) electrophysiological dysfunction of cones, rods, and inner retinal cells. Transgenic mice replicated the human OCT and ERG findings with aged homozygous Q84/Q84 mice showing a stronger phenotype accompanied by further thinning of the outer nuclear layer and photoreceptor layer and highly reduced cone and rod activities, thus supporting severe retinal dysfunction in these mice. In addition, Q84 mice showed progressive accumulation of ATXN3-positive aggregates throughout several retinal layers and depletion of cones alongside the disease course. TEM analysis of aged Q84/ Q84 mouse retinas supported the ATXN3 aggregation findings by revealing the presence of high number of negative electron dense puncta in ganglion cells, inner plexiform and inner nuclear layers, and showed further thinning of the outer plexiform layer, thickening of the retinal pigment epithelium and elongation of apical microvilli.Our results indicate that retinal alterations detected by non-invasive eye examination using OCT and ERG could represent a biological marker of disease progression and severity in patients with SCA3.
Filiaciones:
Toulis V:
Department of Neurology, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona 08028, Spain
CIBERER, ISCIII, Universitat de Barcelona, Barcelona 08028, Spain
Casaroli-Marano R:
Service of Ophthalmology, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona 08036, Spain
Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona 08036, Spain
Department of Surgery, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona 08036, Spain
Camós-Carreras A:
Service of Ophthalmology, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona 08036, Spain
Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona 08036, Spain
Figueras-Roca M:
Service of Ophthalmology, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona 08036, Spain
Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona 08036, Spain
Sánchez-Dalmau B:
Service of Ophthalmology, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona 08036, Spain
Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona 08036, Spain
Department of Surgery, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona 08036, Spain
Muñoz E:
Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona 08036, Spain
Department of Surgery, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona 08036, Spain
Service of Neurology, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona 08036, Spain
European Reference Network of Rare Neurological Diseases (ERN-RND), Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona 08036, Spain
Ashraf NS:
Department of Neurology, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Ferreira AF:
Departamento de Biologia, Faculdade de Ciências e Tecnologia, Universidade dos Açores, Portugal
Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
Khan N:
Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48109, USA
Marfany G:
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona 08028, Spain
CIBERER, ISCIII, Universitat de Barcelona, Barcelona 08028, Spain
Institute of Biomedicine - Institut de Recerca Sant Joan de Déu (IBUB - IRSJD), Universitat de Barcelona, Barcelona 08028, Spain
do Carmo Costa M:
Department of Neurology, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Green Published, Green Submitted, gold
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