Several
neuronal ceroid lipofuscinoses (NCL) show storage of
subunit c of mitochondrial ATP synthase. The neurodegenerative process, however, remains obscure. We previously reported a decreased basal
ATP synthase activity in fibroblasts from late-infantile NCL (CLN2) and juvenile NCL (CLN3) patients. We have now extended the study of the
ATP synthase system to an ovine NCL (a model for the late-infantile NCL variant, CLN6) and the infantile NCL (CLN1). In fibroblasts from healthy sheep, active regulation of
ATP synthase in response to cellular energy demand was present similar to human cells:
ATP synthase was down-regulated under conditions of
anoxia or functional uncoupling and was up-regulated in response to
calcium. In fibroblasts from NCL sheep, basal
ATP synthase activity was slightly elevated and down-regulation in response to
anoxia or uncoupling of mitochondria also occurred.
Calcium produced an unexpected down-regulation to 55% of basal activity. Activities of respiratory chain
enzymes did not differ between healthy and NCL sheep. In fibroblasts from CLN1 patients, basal
ATP synthase activity was reduced and regulation of the
enzyme was absent. Activities of respiratory chain complexes II and IV were reduced. The defect of
ATP synthase regulation found in fibroblasts from NCL sheep and infantile NCL patients is different from the
ATP synthase deficiencies demonstrated in late-infantile and juvenile NCL, but problems of mitochondrial energy production, if also expressed in brain, would be a common feature of several NCL forms. Deficient
ATP supply could result in degeneration of neurons, especially in those with high energy requirements.