Batten disease, one of the most devastating types of neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3. Here, we show that CLN3 is a vesicular trafficking hub connecting the Golgi and lysosome compartments. Proteomic analysis reveals that CLN3 interacts with several endo-lysosomal trafficking proteins, including the cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates the targeting of lysosomal enzymes to lysosomes. CLN3 depletion results in mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation. Conversely, CLN3 overexpression promotes the formation of multiple lysosomal tubules, which are autophagy and CI-M6PR-dependent, generating newly formed proto-lysosomes. Together, our findings reveal that CLN3 functions as a link between the M6P-dependent trafficking of lysosomal enzymes and lysosomal reformation pathway, explaining the global impairment of lysosomal function in Batten disease.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10317969 | PMC |
http://dx.doi.org/10.1038/s41467-023-39643-7 | DOI Listing |
Orphanet J Rare Dis
December 2024
Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.
Background: This study evaluated the clinical characteristics of neuronal ceroid lipofuscinosis type 7 or CLN7 disease spectrum to characterize the clinical, electrophysiologic and neuroimaging phenotypes.
Methods: We performed a single-center cross sectional data collection along with retrospective medical chart review in patients with a genetic diagnosis of CLN7. This study received ethical approval by the University of Texas Southwestern Medical Center Institutional Review Board.
Transl Psychiatry
December 2024
The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, He'nan, China.
The infantile neuronal ceroid lipofuscinosis, also called CLN1 disease, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). Identifying the depalmitoylation substrates of PPT1 is crucial for understanding CLN1 disease. In this study, we found that GABAR, the critical synaptic protein essential for inhibitory neurotransmission, is a substrate of PPT1.
View Article and Find Full Text PDFInt J Pharm
December 2024
Great Ormond Street Institute of Child Health, University College London, London WC1E 6BT, UK. Electronic address:
The neuronal ceroid lipofuscinoses, commonly known as Batten disease, are a group of lysosomal storage disorders affecting children. There is extensive central nervous system and retinal degeneration, resulting in seizures, vision loss and a progressive cognitive and motor decline. Enzyme replacement and gene therapies are being developed, and mRNA and oligonucleotide therapies are more recently being considered.
View Article and Find Full Text PDFBackground: Bluetongue virus serotype 3 (BTV-3) was detected for the first time in cattle and sheep in southern England in 2023, the first UK BTV incursion for more than 15 years. Clinical signs were not observed, yet severe clinical disease and mortality were reported during recent BTV-3 outbreaks in northern Europe.
Methods: To investigate the clinical disease and infection kinetics associated with this UK BTV-3 strain, five British sheep were infected with a UK BTV-3 isolate using Culicoides biting midges.
J Neurol Sci
December 2024
Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India. Electronic address:
Background: Neuronal ceroid lipofuscinoses (NCLs) are progressive, autosomal recessive lysosomal storage disorders primarily affecting children, marked by seizures, cognitive decline, motor regression, and visual impairment. Limited genetic data exist for South Asian populations, with most studies relying on enzymatic assays or electron microscopy. This study explores the genetic spectrum of NCL and genotype-phenotype correlations in a cohort from South India.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!