Ubap1 knock-in mice reproduced the phenotype of SPG80.
J Hum Genet
; 67(12): 679-686, 2022 Dec.
Article
in En
| MEDLINE
| ID: mdl-35962060
ABSTRACT
SPG80 is a neurodegenerative disorder characterized by a pure type of juvenile-onset hereditary spastic paraplegia and is caused by a heterozygous mutation of the UBAP1 (ubiquitin-associated protein 1) gene. UBAP1 is one of the subunits of the endosomal sorting complex required for transport I and plays a role in endosome sorting by binding to ubiquitin-tagged proteins. In this study, we generated novel Ubap1+/E176Efx23 knock-in mice, in which the SOUBA domain of Ubap1 was completely deleted with the UMA domain being intact, as an animal model of SPG80. The knock-in mice with this heterozygous Ubap1 truncated mutation appeared normal at birth, but they developed progressive hind limb dysfunction several months later. Molecular pathologically, loss of neurons in the spinal cord and accumulation of ubiquitinated proteins were observed in Ubap1+/E176Efx23 knock-in mice. In addition, changes in the distributions of Rab5 and Rab7 in the spinal cord suggest that this mutation in Ubap1 disturbs endosome-mediated vesicular trafficking. This is the first report of a mouse model that reproduces the phenotype of SPG80. Our knock-in mice may provide a clue for understanding the molecular pathogenesis underlying UBAP1-related HSP and screening of therapeutic agents.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Spastic Paraplegia, Hereditary
/
Carrier Proteins
Limits:
Animals
Language:
En
Journal:
J Hum Genet
Journal subject:
GENETICA MEDICA
Year:
2022
Document type:
Article
Affiliation country: