RT info:eu-repo/semantics/article
T1 Apolipoprotein D-mediated preservation of lysosomal function promotes cell survival and delays motor impairment in Niemann-Pick type A disease
A1 Sánchez Romero, Diego
A1 Fadrique-Rojo, Cristian
A1 Pascua Maestro, Raquel
A1 Corraliza Gómez, Miriam
A1 Ledesma, María D.
A1 Schuchman, Edward H.
A1 Ganfornina Álvarez, María Dolores
AB Lysosomal Storage Diseases (LSD) are genetic diseases causing systemic and nervous system dysfunction. Theglia-derived lipid binding protein Apolipoprotein D (ApoD) is required for lysosomal functional integrity in glialand neuronal cells, ensuring cell survival upon oxidative stress or injury. Here we test whether ApoD counteractsthe pathogenic consequences of a LSD, Niemann Pick-type-A disease (NPA), where mutations in the acidsphingomyelinase gene result in sphingomyelin accumulation, lysosomal permeabilization and early-onsetneurodegeneration. We performed a multivariable analysis of behavioral, cellular and molecular outputs in 12and 24 week-old male and female NPA model mice, combined with ApoD loss-of-function mutation. Lack ofApoD in NPA mice accelerates cerebellar-dependent motor deficits, enhancing loss of Purkinje neurons. Westudied ApoD expression in brain sections from a NPA patient and age-matched control, and the functionalconsequences of ApoD supplementation in primary human fibroblasts from two independent NPA patients andtwo control subjects. Cell viability, lipid peroxidation, and lysosomal functional integrity (pH, Cathepsin B activity,Galectin-3 exclusion) were examined. ApoD is endogenously overexpressed in NPA patients and NPAmouse brains and targeted to lysosomes of NPA patient cells, including Purkinje neurons and cultured fibroblasts.The accelerated lysosomal targeting of ApoD by oxidative stress is hindered in NPA fibroblasts, contributingto NPA lysosomes vulnerability. Exogenously added ApoD reduces NPA-prompted lysosomal permeabilizationand alkalinization, reverts lipid peroxides accumulation, and significantly increases NPA cellsurvival. ApoD administered simultaneously to sphingomyelin overload results in complete rescue of cell survival.Our results reveal that ApoD protection of lysosomal integrity counteracts NPA pathology. ApoD supplementationcould significantly delay not only the progression of NPA disease, but also of other LSDs through itsbeneficial effects in lysosomal functional maintenance.
SN 0969-9961
YR 2020
FD 2020
LK https://uvadoc.uva.es/handle/10324/80440
UL https://uvadoc.uva.es/handle/10324/80440
LA spa
NO Neurobiol Dis. 2020 Oct;144:105046
DS UVaDOC
RD 05-mar-2026