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Dissecting a neuron-to-liver crosstalk to modulate lipid metabolism in Batten disease

19th national competition for scientific and technical research

Rare diseases

Senior Researcher : Juan Pedro Bolaños Hernández


Neuronal ceroid lipofuscinoses (NCL), known as Batten disease, are the most common of the rare neurodegenerative disorders in children. To date, defects in thirteen different genes, coding for different sub-cellular located proteins, have been identified in NCL patients. Despite the genetic heterogeneity, Batten diseases are grouped together based on clinical similarities and broadly uniform neuropathological features, including accumulation of ceroids and lipofuscin in lysosomes, as well as profound neurodegeneration and widespread gliosis. Amongst these, the incidence of Cln7 disease, caused by mutation in MFSD8 gene, is the highest in southern and Mediterranean Europe. CLN7/MFSD8 encodes a lysosomal membrane glycoprotein with unknown function. Lysosomes are the only organelles able to hydrolyse triacylglycerols, which fuels the mitochondria for energy generation. The autophagic machinery provides TGs to the lysosomes through a process known as lipophagy. Although defective autophagy has been previously related with Cln7 disease, Cln7 role in lipid metabolism is unknown, particularly in lipophagy.

In this proposal we hypothesize that disruption of lipid metabolism and lipophagy links neuronal death and Cln7-mediated Batten disease. To address this, we will (1) study lipid metabolism and lipophagy in Cln7 knockout (Cln7-KO) mice, (2) elucidate whether Cln7 loss in the hypothalamus disrupts lipid liver metabolism and lipophagy in vivo and (3) whether liver lipophagy is rescued by uncoupling the liver from the hypothalamus in Cln7-KO mice. During the first nine months of project execution, we have obtained experimental data from different techniques, such as western blotting and immunocytochemistry in Cln7-KO mice fibroblasts, liver, brown fat and brain, to stablish a connection between the brain and the metabolism of the peripheral tissues. Thus, our data show that Cln7 deficiency in the hypothalamus damages liver lipophagy resulting in fat accumulation. Ongoing work is being developed to validate these observations using robust metabolic and in vivo uncoupling approaches.


Scientific Production
Magazine Articles 4
Communications at national conferences 1
Communications at international conferences 6


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