Characterisation of a model of ALS8 in the rat
dc.contributor.advisor
Skehel, Paul
dc.contributor.advisor
Jackson, Mandy
dc.contributor.advisor
Skehel, Paul
dc.contributor.author
Murage, Brenda
dc.contributor.sponsor
Euan Macdonald Centre
en
dc.date.accessioned
2023-01-18T12:43:58Z
dc.date.available
2023-01-18T12:43:58Z
dc.date.issued
2023-01-18
dc.description.abstract
Amyotrophic lateral sclerosis 8 (ALS8) is a late-onset slow-progressing form of motor neurone disease caused by a missense mutation replacing cytosine with thymine in the VAMP-associated protein B (vapB) gene, leading to a proline to serine replacement at position 56 (P56S) in the protein. The vapB protein is ubiquitously expressed in humans and located on the endoplasmic reticulum (ER). It is involved in intracellular signalling through two phenylalanine in a fatty acidic tract (FFAT)-like motifs on target proteins binding the major sperm protein domain (MSP) which can also cleave for extracellular signalling. The vapBP56S mutation interferes with MSP cleavage and vapB function by preventing cleavage of the MSP domain. CRISPR with long single stranded DNA inducing conditional knockout alleles (CLICK) was used to generate founders of a colony, with heterozygous (vapBP56S/+), homozygous (vapBP56S/P56S), and knockout (vapB-/-) offspring. A cohort was aged to 17-18 months in a longitudinal study with gait being assessed at 6, 12, and 18 months. Male vapBP56S/P56S, female vapBP56S/P56S and female vapB-/- exerted less pressure on their paws at 18 months. Tissue was collected at 18 months and analysed. There were fewer motor neurons (MN) in the lumbar spinal cord of vapBP56S/+ and vapBP56S/P56S, and MN were smaller in vapBP56S/P56S. TDP-43 pathology was present in vapB-/- motor neurons, and syntaxin 1A signal was reduced in lumbar spinal homogenates, but glial activation was absent. These results show that this rat model could help to provide insight into the initiation and propagation of ALS8.
en
dc.identifier.uri
https://hdl.handle.net/1842/39724
dc.identifier.uri
http://dx.doi.org/10.7488/era/2973
dc.language.iso
en
en
dc.publisher
The University of Edinburgh
en
dc.subject
ALS8
en
dc.subject
Amyotrophic lateral sclerosis 8
en
dc.subject
motor neurone disease
en
dc.subject
missense mutation
en
dc.subject
P56S
en
dc.subject
endoplasmic reticulum
en
dc.subject
ER
en
dc.subject
fatty acidic tract
en
dc.subject
FFAT
en
dc.subject
major sperm protein domain
en
dc.subject
MSP
en
dc.title
Characterisation of a model of ALS8 in the rat
en
dc.type
Thesis or Dissertation
en
dc.type.qualificationlevel
Doctoral
en
dc.type.qualificationname
PhD Doctor of Philosophy
en
Files
Original bundle
1 - 1 of 1
- Name:
- MurageB_2022.pdf
- Size:
- 4.4 MB
- Format:
- Adobe Portable Document Format
- Description:
This item appears in the following Collection(s)