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

Chen, Jacinda; Bennett, David A.; Xu, Yimeng; Simoes, Sabrina; Liang, Feng; DeFreitas, Laura; Hwang, Robert; Montesinos, Jorge; Lee, Joseph H.; Area‐Gómez, Estela; Nandakumar, Renu; Vardarajan, Badri N.; Marquer, Catherine

doi:10.1016/j.ebiom.2023.104628

Cited by 4 publications

(2 citation statements)

References 67 publications

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“…This targeted analysis confirmed a global decrease in BMP species at 5 dpf in MUT1 larvae, with the highly abundant BMP 22:6_22:6 showing the most important -fold change ( Fig 7C ). Interestingly, whereas individual cholesterol ester species (CE) changes between MUT1 and WT1 larvae were not significant, the summed level of cholesterol esters was significantly increased in MUT1 larvae ( Fig 7D ), being in perfect agreement with results obtained in isolated late endosome/lysosome compartments from the frozen human prefrontal cortex tissue ( 37 ). Furthermore, triacylglycerides, and hexosyl- and lactosylceramides also showed (non-significant) elevations in MUT1 larvae.…”

Section: Resultssupporting

confidence: 87%

CLN3 deficiency leads to neurological and metabolic perturbations during early development

Heins-Marroquin,

Singh,

Perathoner

et al. 2024

Life Sci. Alliance

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Juvenile neuronal ceroid lipofuscinosis (or Batten disease) is an autosomal recessive, rare neurodegenerative disorder that affects mainly children above the age of 5 yr and is most commonly caused by mutations in the highly conservedCLN3gene. Here, we generatedcln3morphants and stable mutant lines in zebrafish. Although neither morphant nor mutantcln3larvae showed any obvious developmental or morphological defects, behavioral phenotyping of the mutant larvae revealed hyposensitivity to abrupt light changes and hypersensitivity to pro-convulsive drugs. Importantly, in-depth metabolomics and lipidomics analyses revealed significant accumulation of several glycerophosphodiesters (GPDs) and cholesteryl esters, and a global decrease in bis(monoacylglycero)phosphate species, two of which (GPDs and bis(monoacylglycero)phosphates) were previously proposed as potential biomarkers forCLN3disease based on independent studies in other organisms. We could also demonstrate GPD accumulation in human-induced pluripotent stem cell–derived cerebral organoids carrying a pathogenic variant forCLN3. Our models revealed that GPDs accumulate at very early stages of life in the absence of functional CLN3 and highlight glycerophosphoinositol and BMP as promising biomarker candidates for pre-symptomaticCLN3disease.

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Section: Resultssupporting

confidence: 87%

CLN3 deficiency leads to neurological and metabolic perturbations during early development

Heins-Marroquin,

Singh,

Perathoner

et al. 2024

Life Sci. Alliance

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“…In this context, the CLN3 protein is located in many cellular compartments, including the endo-lysosomal pathway and the Golgi complex. However, although its exact function is not fully understood, it has been linked to intracellular trafficking through interactions with Rab7A and protein secretion processes [267,268].…”

Section: Autophagy Pathway In Neuronal Ceroid Lipofuscinosesmentioning

confidence: 99%

Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases

Uribe-Carretero,

Rey,

Fuentes

et al. 2024

Biology

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Lysosomes are the main organelles responsible for the degradation of macromolecules in eukaryotic cells. Beyond their fundamental role in degradation, lysosomes are involved in different physiological processes such as autophagy, nutrient sensing, and intracellular signaling. In some circumstances, lysosomal abnormalities underlie several human pathologies with different etiologies known as known as lysosomal storage disorders (LSDs). These disorders can result from deficiencies in primary lysosomal enzymes, dysfunction of lysosomal enzyme activators, alterations in modifiers that impact lysosomal function, or changes in membrane-associated proteins, among other factors. The clinical phenotype observed in affected patients hinges on the type and location of the accumulating substrate, influenced by genetic mutations and residual enzyme activity. In this context, the scientific community is dedicated to exploring potential therapeutic approaches, striving not only to extend lifespan but also to enhance the overall quality of life for individuals afflicted with LSDs. This review provides insights into lysosomal dysfunction from a molecular perspective, particularly in the context of human diseases, and highlights recent advancements and breakthroughs in this field.

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Upregulation of peroxisome proliferator-activated receptor γ with resorcinol alleviates reactive oxygen species generation and lipid accumulation in neuropathic lysosomal storage diseases

Kim,

Kim

2024

The International Journal of Biochemistry & Cell Biology

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

Cited by 4 publications

References 67 publications

CLN3 deficiency leads to neurological and metabolic perturbations during early development

CLN3 deficiency leads to neurological and metabolic perturbations during early development

Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases

Upregulation of peroxisome proliferator-activated receptor γ with resorcinol alleviates reactive oxygen species generation and lipid accumulation in neuropathic lysosomal storage diseases

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