Potential causes of lysosomal defects in neurological disorders. (A) Presenilin 1 (PS1) KO or FAD mutations impair N-glycosylation of V0a1 (V0a1 subunit of v-ATPase). In the absence of N-glycosylation, V0a1 does not traffic to lysosomes, causing defects in lysosomal acidification. Based on Lee et al. (2010). Pink and dark pink indicate differences in intralysosomal H⁺ concentrations. (B) LIMP-2 mutations impair trafficking of β-glucocerebrosidase (β-GC) to lysosomes in action myoclonus-renal failure syndrome (AMRF). Based on Berkovic et al. (2008) and Blanz et al. (2010). (C) Lysosomal Ca²⁺ release via TRPML1 channels triggers lysosomal fusion. (D) Mutations in TRPML1 result in impaired lysosomal Ca²⁺ release and impaired lysosomal fusion in mucolipidosis IV (MLIV). Based on LaPlante et al. (2004). (E) PS1 KO or FAD mutations impair ER Ca²⁺ leak and result in reduced Ca²⁺ loading into lysosomes. Reduced lysosomal Ca²⁺ levels result in impaired lysosomal fusion. Based on Tu et al. (2006) and Coen et al. (2012). (C–E) Gray and dark gray correspond to different Ca²⁺ concentrations in the ER and lysosomes.