Research projects

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 project we proposed that defective lipophagy is the cause of neuronal death characteristic of Batten disease. To this end, we have studied (1) whether lipophagy is affected in Cln7-deficient (Cln7-KO) mice, (2) whether loss of Cln7 in the brain alters lipophagy in the liver, (3) and whether defects in hepatic lipophagy are rescued by uncoupling the liver from the brain. The results obtained show that Cln7 deficiency in the brain, specifically in the median basal hypothalamus (MBH), severely alters autophagic flow in this tissue, affecting peripheral lipid metabolism. Moreover, the alteration of MBH damages hepatic lipophagy and that of brown adipose tissue, which causes accumulation of fat in these organs and alterations in the thermogenic response. These results strongly suggest the existence of a connection between the brain and peripheral tissues that is damaged in Batten disease and open new horizons in the search for strategies against this type of devastating disease.