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Lysosomal alterations and decreased electrophysiological activity in CLN3 disease patient-derived cortical neurons
Citation
Chear, S and Perry, S and Wilson, R and Bindoff, A and Talbot, J and Ware, TL and Grubman, A and Vickers, JC and Pebay, A and Ruddle, JB and King, AE and Hewitt, AW and Cook, AL, Lysosomal alterations and decreased electrophysiological activity in CLN3 disease patient-derived cortical neurons, Disease Models & Mechanisms, 15, (12) pp. 1-15. ISSN 1754-8403 (2022) [Refereed Article]
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Abstract
CLN3 disease is a lysosomal storage disorder associated with fatal neurodegeneration that is
caused by mutations in CLN3, with most affected individuals carrying at least one allele with
a 966 bp deletion. Using CRISPR/Cas9, we corrected the 966 bp deletion mutation in human
induced pluripotent stem cells (iPSCs) of a compound heterozygous patient (CLN3 Δ 966 bp
and E295K). We differentiated these isogenic iPSCs, and iPSCs from an unrelated healthy
control donor to neurons and identified disease-related changes relating to protein synthesis,
trafficking and degradation, and in neuronal activity which were not apparent in CLN3-
corrected or healthy control neurons. CLN3 neurons showed numerous membrane-bound
vacuoles containing diverse storage material, and hyperglycosylation of the lysosomal
LAMP1 protein. Proteomic analysis showed increase in lysosomal-related proteins and many
ribosomal subunit proteins in CLN3 neurons that was accompanied by downregulation of
proteins related to axon guidance and endocytosis. CLN3 neurons also had lower
electrophysical activity as recorded using microelectrode arrays. These data implicate
interrelated pathways in protein homeostasis and neurite arborization as contributing to
CLN3 disease, and which could be potential targets for therapy.
Item Details
| Item Type: | Refereed Article |
|---|---|
| Keywords: | Juvenile Neuronal Ceroid Lipofuscinosis, Batten disease, dementia, induced pluripotent stem cells, microelectrode array, proteomics |
| Research Division: | Biological Sciences |
| Research Group: | Biochemistry and cell biology |
| Research Field: | Cell development, proliferation and death |
| Objective Division: | Health |
| Objective Group: | Clinical health |
| Objective Field: | Prevention of human diseases and conditions |
| UTAS Author: | Chear, S (Ms Sueanne Chear) |
| UTAS Author: | Perry, S (Dr Sharn Perry) |
| UTAS Author: | Wilson, R (Dr Richard Wilson) |
| UTAS Author: | Bindoff, A (Mr Aidan Bindoff) |
| UTAS Author: | Talbot, J (Dr Jana Talbot) |
| UTAS Author: | Vickers, JC (Professor James Vickers) |
| UTAS Author: | King, AE (Professor Anna King) |
| UTAS Author: | Hewitt, AW (Professor Alex Hewitt) |
| UTAS Author: | Cook, AL (Associate Professor Tony Cook) |
| ID Code: | 154486 |
| Year Published: | 2022 |
| Deposited By: | Wicking Dementia Research and Education Centre |
| Deposited On: | 2022-12-05 |
| Last Modified: | 2022-12-15 |
| Downloads: | 0 |
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