Is autophagy altered in Neuronal Ceroid Lipofuscinoses (NCL) disease?

GUELBERT, GUILLERMO; CISMONDI, INÉS ADRIANA; BECERRA, ADRIANA; PESAOLA, FAVIO; VENIER, ANA CLARA; DE PAUL, ANA LUCÍA; VAZQUEZ, JUAN CARLOS G.; FERNANDEZ, ELMER; GUELBERT, NORBERTO; NOHER, INÉS

Sydney

Congreso; 14th International Congress of Inborn Error of Metabolism 2021; 2021

Autophagy is a degradative cell process to recycle obsolete cellular constituents, and eliminate damaged organelles and protein aggregates. These substrates reach lysosomes by several mechanisms, including delivery within endosomes and autophagosomes. Digestion involves dynamic interactions among compartments of the autophagic and endocytic pathways. Neurons are particularly vulnerable to disruptions of these interactions, especially as the brain ages. Dysregulated autophagy has been identified in almost every late-onset neurodegenerative disorder, and similar defects are now being recognized in neuronal ceroid lipofuscinoses disease (NCL Disease), a sub-group of Lysosomal disorders (LD) with childhood-onset neurodegeneration. To date, 13 NCL disease-causing genes havebeen identified. Of these genes several encode lysosomal proteins, including soluble enzymes/proteins (CLN1/PPT1, CLN2/TPP1, CLN5, CLN10/CTSD and CLN13/CTSF); membrane proteins (CLN3, CLN7/MFSD8 and CLN12/ATP13A2); endoplasmic reticulum membrane proteins (CLN6 and CLN8); cytosolic proteins (CLN4/DNAJC5 and CLN14/KCTD7) and expression in the secretory pathway (CLN11/GRN). Methods: 1) Bibliography evidences research on autophagy in NCL disease, 2) Phenotypic and genomic study of 5 children with excluded NCL. Results: 1) The evidences were systematized. 2) An ad hoc autophagy gene-panel was constructed. 3) 3/5 children showed 6 highly infrequent autophagy DNA variants: 2 in TBCK; 1 in DMXL2, 1 in TSC1, and 2 in TSC2. Conclusion: Autophagy disruption in NCL-like disease needs further genomic and biochemical investigation.