Batten disease is the most common form of Neuronal ceroid-lipofuscinoses (NCL), the most frequently occurring group of progressive neurodegenerative diseases in children with an incidence as high as one in 12,500 live births, and with about 440,000 carriers in the USA. These disorders are autosomal recessive with progression characterised by visual problems leading to blindness, decline in mental abilities, increased severity of untreatable seizures, blindness, loss of motor skills and premature death. Although the gene responsible for Batten disease, CLN3, was positionally cloned in 1995, the function of Cln3p is still unknown. We previously reported that the yeast Saccharomyces cerevisiae contains a homolog to Cln3p, designated Btn1p, and that the human Cln3p complemented the pH-dependent resistance to D-(−)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol in btn1-D yeast mutants. Furthermore, the severity of Batten disease in humans and the degree of ANP resistance in yeast are related when the equivalent changes in Cln3p and Btn1p are compared. This establishes that the yeast and human protein perform the same function in the cell.

Examination of the expression of virtually all yeast genes by DNA microarray analysis of BTN1 and btn1-D strains revealed differential expression of two genes, HSP30 and BTN2 (YGR142W). Expression of both HSP30, a down regulator of plasma membrane ATPase, and BTN2 is increased in btn1-D strains.

Our biochemical studies have revealed that the pH-dependent resistance to ANP of btn1-D strains results from an elevated ability to acidify the growth medium. This increased rate of acidification is due to an increased activity of the plasma membrane ATPase, during the early phases of growth. Yeast lacking Btn1p have a vacuolar pH of 5.8, as compared to normal, 6.2, in the early phases of growth. As btn1-D strains grow, the elevated plasma membrane ATPase activity and the decrease in vacuolar pH are apparently normalised. A link between vacuolar pH and plasma membrane ATPase activity was confirmed in strains which have a disrupted vacuolar ATPase, which elevates vacuolar pH to pH 6.9, and results in a lower than normal plasma membrane ATPase activity. We propose that btn1-D strains have increased expression of HSP30 in response to an elevated plasma membrane ATPase activity due to an altered regulation of vacuolar pH. The increased expression of BTN2, a previously unknown gene that has homology to human HOOK1, whose Drosophila homolog is a novel endocytic component may suggest a role for this protein in balancing intracellular pH.