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-Delta 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-Delta 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-Delta 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-Delta strains and diminished growth of btn1-Delta, hsp30-Delta, and btn2-Delta strains at low pH reinforce our view that altered pH homeostasis is the underlying cause of Batten disease.
Chattopadhyay
S
S
Center for Aging and Developmental Biology, University of Rochester Medical School, Rochester, New York 14642, USA.
Muzaffar
N E
NE
Sherman
F
F
Pearce
D A
DA
D003470:Culture Media; D016213:Cyclins; D003600:Cytosol / Q000378:metabolism; D005656:Fungal Proteins / Q000032:analysis / Q000235:genetics*; D050890:HSP30 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics*; D006706:Homeostasis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics*; D018832:Molecular Chaperones; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000382:microbiology*; D006180:Proton-Translocating ATPases / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D013011:Sorbic Acid; D014617:Vacuoles / Q000378:metabolism; D015003:Yeasts / Q000235:genetics* / Q000254:growth & development
C105199:CLN3 protein, human; D003470:Culture Media; D016213:Cyclins; D005656:Fungal Proteins; D050890:HSP30 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; C489809:YHC3 protein, S cerevisiae; D006180:Proton-Translocating ATPases; D013011:Sorbic Acid