Viral delivery of a microRNA to Gba to the mouse central nervous system models neuronopathic Gaucher disease

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved..

Pathological mutations in GBA, encoding lysosomal glucocerebrosidase (GCase), cause Gaucher disease (GD). GD is a multi-system disease with great phenotypic variation between individuals. It has been classified into type 1 with primarily peripheral involvement and types 2 and 3 with varying degrees of neurological involvement. GD is characterized by decreased GCase activity and subsequent accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Current murine models of neuronopathic GD mostly replicate the severe aspects of the neurological symptoms developing rapid progression and early lethality, thus presenting a short window for therapeutic testing. In order to develop a model of chronic neuronopathic GD, we reduced GCase in the central nervous system (CNS) of a mild GD mouse model (GbaD409V/D409V) via intracerebroventricular administration of an adeno-associated virus encoding a microRNA to Gba (AAV-GFP-miR-Gba). GbaD409V/D409V mice have significantly reduced GCase activity and increased substrate accumulation in the CNS. Phenotypically, these mice partially recapitulate features of mild type 1 GD. Their neurological examination reveals cognitive impairment with normal motor features. Administration of AAV-GFP-miR-Gba into GbaD409V/D409V pups in the CNS caused progressive lipid substrate accumulation. Phenotypically, AAV1-GFP-miR-Gba-treated mice were indistinguishable from their littermates until 10 weeks of age, when they started developing progressive neurological impairments, including hyperactivity, abnormal gait, and head retroflexion. Importantly, these impairments can be prevented by simultaneous administration of a miR-resistant GBA, demonstrating that the pathological effects are specifically due to Gba mRNA reduction. This novel model of neuronopathic GD offers several advantages over current models including slower progression of neurological complications and an increased lifespan, which make it more amenable for therapeutic testing.

Medienart:

E-Artikel

Erscheinungsjahr:

2019

Erschienen:

2019

Enthalten in:

Zur Gesamtaufnahme - volume:130

Enthalten in:

Neurobiology of disease - 130(2019) vom: 21. Okt., Seite 104513

Sprache:

Englisch

Beteiligte Personen:

Jackson, Kasey L [VerfasserIn]
Viel, Catherine [VerfasserIn]
Clarke, Jennifer [VerfasserIn]
Bu, Jie [VerfasserIn]
Chan, Monyrath [VerfasserIn]
Wang, Bing [VerfasserIn]
Shihabuddin, Lamya S [VerfasserIn]
Sardi, S Pablo [VerfasserIn]

Links:

Volltext

Themen:

AAV-mediated microRNA reduction
Ataxia
EC 3.2.1.45
Gba
Glucosylceramidase
Journal Article
MicroRNAs
Neuronopathic Gaucher disease
Research Support, Non-U.S. Gov't

Anmerkungen:

Date Completed 24.03.2020

Date Revised 24.03.2020

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.nbd.2019.104513

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM298480344