PXD032191

PXD032191 is an original dataset announced via ProteomeXchange.

Title	Lysosomal alterations and altered electrophysiological activity in atypical juvenile neuronal ceroid lipofuscinoses (CLN3 1 kb deletion, E295K) patient-derived cortical neurons
Description	Juvenile neuronal ceroid lipofuscinoses (JNCL) is a lysosomal storage disorder associated with fatal neurodegeneration that is caused by mutations in CLN3. Most individuals with JNCL carry at least one allele with 1 kb deletion in CLN3 which results in the deletion of exons 7 and 8. There is a need for more physiologically relevant human cell-based JNCL models to better understand the cellular changes during the disease process. Using CRISPR/Cas9, we have corrected a 1 kb deletion mutation in human induced pluripotent stem cells (iPSC) of a compound heterozygous patient (CLN3 Δ1 kb and E295K), to generate an isogenic control to be used for disease modeling along with the unedited CLN3 patient iPSCs. iPSC-derived neurons carrying this particular CLN3 mutation, CLN3 neurons, had lower levels of spike, burst and network burst activity for most of the culture period. Proteomics analysis showed downregulation of proteins related to axon guidance and endocytosis on day in vitro (DIV) 14 and 42 in CLN3 neurons. This was accompanied by an increase in lysosomal-related proteins in CLN3 neurons. Western blot analysis of LAMP1 expression revealed a new finding where LAMP1 was hyperglycosylated in CLN3 neurons on DIV 14, 28 and 42, which was not apparent in control neurons. Ultrastructural analysis of CLN3 neurons showed numerous membrane-bound vacuoles containing diverse types of storage material, ranging from curvilinear deposits, multilamellar structures to osmiophilic deposits. Our findings suggest alterations in lysosomal function and neurodevelopment involving axon guidance and synaptic transmission in CLN3-deficient neuronal derivatives, which could be potential targets for therapy.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:55:21.893.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Richard Wilson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-11 01:30:12	ID requested
1	2022-12-07 05:43:46	announced
⏵ 2	2023-11-14 08:55:22	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: lysosomal storage disorder, neurological disease models,Juvenile neuronal ceroid lipofuscinoses, human induced pluripotent stem cells

Dr Richard Wilson
contact affiliation	Proteomics facility, Central Science Laboratory, University of Tasmania
contact email	richard.wilson@utas.edu.au
lab head
Richard Wilson
contact affiliation	University of Tasmania
contact email	richard.wilson@utas.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD032191
     1. Label: PRIDE project
     2. Name: Lysosomal alterations and altered electrophysiological activity in atypical juvenile neuronal ceroid lipofuscinoses (CLN3 1 kb deletion, E295K) patient-derived cortical neurons