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Lysosomal alterations and decreased electrophysiological activity in CLN3 disease patient-derived cortical neurons


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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DOI: doi:10.1242/dmm.049651


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

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