The Yeast Model for Batten Disease: Mutations in btn1, btn2, and hsp30 Alter pH Homeostasis

The BTN1 gene product of the yeast Saccharomyces cerevisiae is 39% identical and 59% similar to human CLN3, which is associated with the neurodegenerative disorder Batten disease. Furthermore, btn1-Δ strains have an elevated activity of the plasma membrane H(+)-ATPase due to an abnormally high vacuolar acidity during the early phase of growth. Previously, DNA microarray analysis revealed that btn1-Δ strains compensate for the altered plasma membrane H(+)-ATPase activity and vacuolar pH by elevating the expression of the two genes HSP30 and BTN2. We now show that deletion of either HSP30 or BTN2 in either BTN1(+) or btn1-Δ strains does not alter vacuolar pH but does lead to an increased activity of the vacuolar H(+)-ATPase. Deletion of BTN1, BTN2, or HSP30 does not alter cytosolic pH but diminishes pH buffering capacity and causes poor growth at low pH in a medium containing sorbic acid, a condition known to result in disturbed intracellular pH homeostasis. Btn2p was localized to the cytosol, suggesting a role in mediating pH homeostasis between the vacuole and plasma membrane H(+)-ATPase. Increased expression of HSP30 and BTN2 in btn1-Δ strains and diminished growth of btn1-Δ, hsp30-Δ, and btn2-Δ strains at low pH reinforce our view that altered pH homeostasis is the underlying cause of Batten disease.