Insight into how SPG80 is caused
An SPG80 mouse that develops HSP-like symptoms has been successfully developed for the first time. Loss of neurons in the spinal cord, protein accumulation and disruption to organelle trafficking were identified. This holds promise for identifying how this form of HSP is caused and for future screening of treatments.
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.
SOURCE: J Hum Genet. 2022 Aug 12. doi: 10.1038/s10038-022-01073-6. Online ahead of print. PMID: 35962060 © 2022. The Author(s).
Ubap1 knock-in mice reproduced the phenotype of SPG80
Keisuke Shimozono 1 , Haitian Nan 1 , Takanori Hata 1 , Kozo Saito 2 , Yeon-Jeong Kim 3 , Hiroaki Nagatomo 4 , Toshihisa Ohtsuka 3 , Schuichi Koizumi 2 , Yoshihisa Takiyama 5 6
1. Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.
2. Department of Neuropharmacology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.
3. Department of Biochemistry, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.
4. Center for Life Science Research, University of Yamanashi, Yamanashi, 409-3898, Japan.
5. Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan. [email protected].
6. Department of Neurology, Fuefuki Central Hospital, Yamanashi, 406-0032, Japan. [email protected].
What can you tell me about Gene therapy for spg84?
Editor’s note: Very little research has been done on SPG84. Here are a couple of references: https://pubmed.ncbi.nlm.nih.gov/35951779/ https://neuromuscular.wustl.edu/spinal/fsp.html#pi4ka
It is unlikely that there is any current research aimed at developing a treatment or cure for this form of HSP.