Biomaterial Database

Juvenile CLN3 disease is a lysosomal cholesterol storage disorder: similarities with Niemann-Pick type C disease. 2023

Jacinda Chen, and Rajesh Kumar Soni, and Yimeng Xu, and Sabrina Simoes, and Feng-Xia Liang, and Laura DeFreitas, and Robert Hwang, and Jorge Montesinos, and Joseph H Lee, and Estela Area-Gomez, and Renu Nandakumar, and Badri Vardarajan, and Catherine Marquer

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York City, NY 10032, USA.

BACKGROUND The most common form of neuronal ceroid lipofuscinosis (NCL) is juvenile CLN3 disease (JNCL), a currently incurable neurodegenerative disorder caused by mutations in the CLN3 gene. Based on our previous work and on the premise that CLN3 affects the trafficking of the cation-independent mannose-6 phosphate receptor and its ligand NPC2, we hypothesised that dysfunction of CLN3 leads to the aberrant accumulation of cholesterol in the late endosomes/lysosomes (LE/Lys) of JNCL patients' brains. METHODS An immunopurification strategy was used to isolate intact LE/Lys from frozen autopsy brain samples. LE/Lys isolated from samples of JNCL patients were compared with age-matched unaffected controls and Niemann-Pick Type C (NPC) disease patients. Indeed, mutations in NPC1 or NPC2 result in the accumulation of cholesterol in LE/Lys of NPC disease samples, thus providing a positive control. The lipid and protein content of LE/Lys was then analysed using lipidomics and proteomics, respectively. RESULTS Lipid and protein profiles of LE/Lys isolated from JNCL patients were profoundly altered compared to controls. Importantly, cholesterol accumulated in LE/Lys of JNCL samples to a comparable extent than in NPC samples. Lipid profiles of LE/Lys were similar in JNCL and NPC patients, except for levels of bis(monoacylglycero)phosphate (BMP). Protein profiles detected in LE/Lys of JNCL and NPC patients appeared identical, except for levels of NPC1. CONCLUSIONS Our results support that JNCL is a lysosomal cholesterol storage disorder. Our findings also support that JNCL and NPC disease share pathogenic pathways leading to aberrant lysosomal accumulation of lipids and proteins, and thus suggest that the treatments available for NPC disease may be beneficial to JNCL patients. This work opens new avenues for further mechanistic studies in model systems of JNCL and possible therapeutic interventions for this disorder. BACKGROUND San Francisco Foundation.

UI	MeSH Term	Description	Entries
D008247	Lysosomes	A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes MEMBRANE FUSION. (From Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed).	Autolysosome,Autolysosomes,Lysosome
D008562	Membrane Glycoproteins	Glycoproteins found on the membrane or surface of cells.	Cell Surface Glycoproteins,Surface Glycoproteins,Cell Surface Glycoprotein,Membrane Glycoprotein,Surface Glycoprotein,Glycoprotein, Cell Surface,Glycoprotein, Membrane,Glycoprotein, Surface,Glycoproteins, Cell Surface,Glycoproteins, Membrane,Glycoproteins, Surface,Surface Glycoprotein, Cell,Surface Glycoproteins, Cell
D011506	Proteins	Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.	Gene Products, Protein,Gene Proteins,Protein,Protein Gene Products,Proteins, Gene
D002784	Cholesterol	The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.	Epicholesterol
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D016464	Lysosomal Storage Diseases	Inborn errors of metabolism characterized by defects in specific lysosomal hydrolases and resulting in intracellular accumulation of unmetabolized substrates.	Lysosomal Enzyme Disorders,Disease, Lysosomal Storage,Diseases, Lysosomal Storage,Disorder, Lysosomal Enzyme,Disorders, Lysosomal Enzyme,Enzyme Disorder, Lysosomal,Enzyme Disorders, Lysosomal,Lysosomal Enzyme Disorder,Lysosomal Storage Disease
D052556	Niemann-Pick Disease, Type C	An autosomal recessive lipid storage disorder that is characterized by accumulation of CHOLESTEROL and SPHINGOMYELINS in cells of the VISCERA and the CENTRAL NERVOUS SYSTEM. Type C (or C1) and type D are allelic disorders caused by mutation of the NPC1 gene, which encodes a protein that mediates intracellular cholesterol transport from LYSOSOMES. Clinical signs include hepatosplenomegaly and chronic neurological symptoms. Type D is a variant in people with a Nova Scotia ancestry.	Niemann-Pick Disease Type C,Niemann-Pick Disease, Type D,Niemann-Pick Type C Disease,Niemann-Pick Type D Disease,Neurovisceral Storage Disease with Vertical Supranuclear Ophthalmoplegia,Niemann-Pick Disease Type D,Niemann-Pick Disease with Cholesterol Esterification Block,Niemann-Pick Disease without Sphingomyelinase Deficiency,Niemann-Pick Disease, Chronic Neuronopathic Form,Niemann-Pick Disease, Nova Scotian,Niemann-Pick Disease, Type C1,Niemann-Pick disease, Subacute Juvenile Form,Niemann-Pick's Disease Type C,Niemann-Pick's Disease Type D,Nova Scotia (Type D) Form of Niemann-Pick Disease,Nova Scotia Niemann-Pick Disease (Type D),Niemann Pick Disease Type C,Niemann Pick Disease Type D,Niemann Pick Disease with Cholesterol Esterification Block,Niemann Pick Disease without Sphingomyelinase Deficiency,Niemann Pick Disease, Chronic Neuronopathic Form,Niemann Pick Disease, Nova Scotian,Niemann Pick Disease, Type C,Niemann Pick Disease, Type C1,Niemann Pick Disease, Type D,Niemann Pick Type C Disease,Niemann Pick Type D Disease,Niemann Pick disease, Subacute Juvenile Form,Niemann Pick's Disease Type C,Niemann Pick's Disease Type D,Nova Scotia Niemann Pick Disease (Type D)
D018832	Molecular Chaperones	A family of cellular proteins that mediate the correct assembly or disassembly of polypeptides and their associated ligands. Although they take part in the assembly process, molecular chaperones are not components of the final structures.	Chaperones, Molecular,Chaperone, Molecular,Molecular Chaperone