Abnormal cathepsin D localization and processing in homozygous CbCln3Δex7/8 cells and Cln3Δex7/8 mice likely reflects altered vesicular trafficking and/or lysosomal pH, which is known to impact cathepsin D processing [14,16]. Indeed, CLN3 overexpression in HEK-293 cells altered lysosomal pH and cathepsin D processing [17], and lysosomal pH homeostasis is disrupted in JNCL [10,15]. It is noteworthy that cathepsin B and the CLN2-encoded enzyme, TPPI, are also altered in JNCL [18-20]. Nevertheless, despite the cathepsin D protein alterations that are observed in homozygous CbCln3Δex7/8 cells, cathepsin D enzymatic activity does not appear to be reduced. Thus, decreased cathepsin D activity is unlikely to account for subunit c accumulation in JNCL.