Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023001%3A_____%2F19%3A00077684" target="_blank" >RIV/00023001:_____/19:00077684 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11110/19:10396325

Výsledek na webu

<a href="https://ajp.amjpathol.org/article/S0002-9440(18)30504-2/fulltext" target="_blank" >https://ajp.amjpathol.org/article/S0002-9440(18)30504-2/fulltext</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ajpath.2018.10.018" target="_blank" >10.1016/j.ajpath.2018.10.018</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment

Popis výsledku v původním jazyce

Farber disease (FD) is a debilitating lysosomal storage disorder characterized by severe inflammation and neurodegeneration. FD is caused by mutations in the ASAH1 gene, resulting in deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency exhibit a broad clinical spectrum. In classic cases, patients develop hepatosplenomegaly, nervous system involvement, and childhood mortality. Ocular manifestations include decreased vision, a grayish appearance to the retina with a cherry red spot, and nystagmus. That said, the full effect of ACDase deficiency on the visual system has not been studied in detail. We previously developed a mouse model that is orthologous for a known patient mutation in Asah1 that recapitulates human FD. Herein, we report evidence of a severe ocular pathology in Asah1(P361R/P361R) mice. Asah1(P361R/P361R) mice exhibit progressive retinal and optic nerve pathology. Through noninvasive ocular imaging and histopathological analyses of these Asah1(P361R/P361R) animals, we revealed progressive inflammation, the presence of retinal dysplasia, and significant storage pathology in various cell types in both the retina and optic nerves. Lipidomic analyses of retinal tissues revealed an abnormal accumulation of ceramides and other sphingolipids. Electroretinograms and behavioral tests showed decreased retinal and visual responses. Taken together, these data suggest that ACDase deficiency leads to sphingolipid imbalance, inflammation, dysmorphic retinal and optic nerve pathology, and severe visual impairment.

Název v anglickém jazyce

Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment

Popis výsledku anglicky

Farber disease (FD) is a debilitating lysosomal storage disorder characterized by severe inflammation and neurodegeneration. FD is caused by mutations in the ASAH1 gene, resulting in deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency exhibit a broad clinical spectrum. In classic cases, patients develop hepatosplenomegaly, nervous system involvement, and childhood mortality. Ocular manifestations include decreased vision, a grayish appearance to the retina with a cherry red spot, and nystagmus. That said, the full effect of ACDase deficiency on the visual system has not been studied in detail. We previously developed a mouse model that is orthologous for a known patient mutation in Asah1 that recapitulates human FD. Herein, we report evidence of a severe ocular pathology in Asah1(P361R/P361R) mice. Asah1(P361R/P361R) mice exhibit progressive retinal and optic nerve pathology. Through noninvasive ocular imaging and histopathological analyses of these Asah1(P361R/P361R) animals, we revealed progressive inflammation, the presence of retinal dysplasia, and significant storage pathology in various cell types in both the retina and optic nerves. Lipidomic analyses of retinal tissues revealed an abnormal accumulation of ceramides and other sphingolipids. Electroretinograms and behavioral tests showed decreased retinal and visual responses. Taken together, these data suggest that ACDase deficiency leads to sphingolipid imbalance, inflammation, dysmorphic retinal and optic nerve pathology, and severe visual impairment.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30109 - Pathology

Projekt

<a href="/cs/project/LM2015091" target="_blank" >LM2015091: Národní centrum lékařské genomiky</a><br>

Návaznosti

N - Vyzkumna aktivita podporovana z neverejnych zdroju

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

American journal of pathology

ISSN

0002-9440

e-ISSN

—

Svazek periodika

189

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

19

Strana od-do

320-338

Kód UT WoS článku

000458713400011

EID výsledku v databázi Scopus

2-s2.0-85060099082