High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

Abstract

Niemann Pick disease type A (NPA), which is caused by loss of function mutations in the acid sphingomyelinase (ASM) gene, is a lysosomal storage disorder leading to neurodegeneration. Yet, lysosomal dysfunction and its consequences in the disease are poorly characterized. Here we show that undegraded molecules build up in neurons of acid sphingomyelinase knockout mice and in fibroblasts from NPA patients in which autophagolysosomes accumulate. The latter is not due to alterations in autophagy initiation or autophagosome-lysosome fusion but because of inefficient autophago-lysosomal clearance. This, in turn, can be explained by lysosomal membrane permeabilization leading to cytosolic release of Cathepsin B. High sphingomyelin (SM) levels account for these effects as they can be induced in control cells on addition of the lipid and reverted on SM-lowering strategies in ASM-deficient cells. These results unveil a relevant role for SM in autophagy modulation and characterize autophagy anomalies in NPA, opening new perspectives for therapeutic interventions.

Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa

“…Interestingly, Nieman-Pick disease is caused by a mutation of this enzyme, and LMP precedes cell death and autophagy blockade in a mouse model of this disease as well as in fibroblasts from affected patients. 10 Photoreceptor cell death in an in vivo model of MNU toxicity is attenuated by valproic acid-induced increases in Hsp70 expression. Interestingly, in that same model, increased oxidative stress results in Hsp70 carbonylation and its subsequent degradation by calpain.…”

“…As in vivo administration of cathepsin inhibitors attenuates cell death in this model, a similar approach could hold therapeutic potential for the treatment of diseases associated with LMP, including Parkinson's disease, Niemann-Pick disease type A and stroke. 7,10,15 Oxidative stress and calpain activation are some of the many stimuli that can induce LMP, and have been observed both in vitro and in vivo. Several pathological processes in the nervous system associated with cell death, including excitotoxicity and ischaemia-reperfusion, have been linked to increased calpain activation.…”

“…[5][6][7] Lysosomal alterations including increases in lysosomal pH and lysosomal membrane permeabilization (LMP) have been demonstrated in Alzheimer's and Parkinson's diseases, 8,9 and mutations in lysosomal enzymes cause defects in autophagy, inducing a marked neurodegenerative phenotype in patients with lysosomal storage disorders. 10 LMP induces the selective translocation of cathepsins to the cytoplasm, triggering caspase-dependent and -independent cell death. [11][12][13] LMP has been implicated in mammary gland involution in physiological conditions, 14 indicating that lysosomal-mediated cell death is not merely a consequence of accidental lysosomal damage.…”

Host sphingomyelin increases West Nile virus infection in vivo

“…A breeding colony was established from a couple of ASM heterozygous C57BL/6 mice kindly donated by Prof. E. H. Schuchman (Mount Sinai School of Medicine, New York) and genotyped as described ( 29 ). Mice were intraperitoneally inoculated with 10 4 PFU per mouse of WNV and monitored daily for signs of infection up to 20 days p.i.…”

“…SM (Santa Cruz Biotechnology, Dallas, TX) was dissolved in ethanol and added to the cells 24 h before infection ( 29 ). D609 (Sigma, St. Louis, MO), SPK-601 (LMV-601; Eurodiagnostico, Madrid, Spain), and MS-209 (dofequidar fumarate; Sigma) were dissolved in DMSO and added to infected cultures 1 h p.i.…”