Disruptive lysosomal-metabolic signaling and neurodevelopmental deficits that precede Purkinje cell loss in a mouse model of Niemann-Pick Type-C disease

Abstract

Purkinje cell (PC) loss occurs at an early age in patients and animal models of Niemann-Pick Type C (NPC), a lysosomal storage disease caused by mutations in the Npc1 or Npc2 genes. Degeneration of PCs occurs early in NPC, however little is known about how NPC1 deficiency affects the postnatal development of PCs. Using the Npc1nmf164 mouse model, we found that NPC1 deficiency significantly affected the postnatal development of PC dendrites and synapses. The developing dendrites of Npc1nmf164 PCs were significantly deficient in mitochondria and lysosomes. Furthermore, anabolic (mTORC1) and catabolic (TFEB) signaling pathways were not only perturbed but simultaneously activated in NPC1-deficient PCs, suggesting a loss of metabolic balance. We also found that mice with conditional heterozygous deletion of the Phosphatase and Tensin Homolog Deleted on Chromosome 10 gene (Pten-cHet), an inhibitor of mTORC1, showed similar early dendritic alterations in PCs to those found in Npc1-deficient mice. However, in contrast to Npc1nmf164 mice, Pten-cHet mice exhibited the overactivation of the mTORC1 pathway but with a strong inhibition of TFEB signaling, along with no dendritic mitochondrial reductions by the end of their postnatal development. Our data suggest that disruption of the lysosomal-metabolic signaling in PCs causes dendritic and synaptic developmental deficits that precede and promote their early degeneration in NPC.

Pathogenic variants inTMEM184Bcause a neurodevelopmental syndrome via alteration of metabolic signaling

“…Cellular phenotypes of NPC include accumulated lipids in the endolysosomal system, similar to what is seen in mouse models of TMEM184B loss-of-function. [35][36][37] In mice containing a disease-associated NPC1 mutation (D1005G) 38 , TFEB is erroneously enriched in the nucleus, similar to what we find in the presence of some TMEM184B patient variants. These commonalities suggest that the pathways leading to NPC and TMEM184B-associated disorders share some downstream effects.…”

“…Cellular phenotypes of NPC include accumulated lipids in the endolysosomal system, similar to what is seen in mouse models of TMEM184B loss-of-function. 35–37 In mice containing a disease-associated NPC1 mutation (D1005G) 38 ,…”