Disruption and therapeutic rescue of a human pluripotent stem cell derived model of Niemann Pick type C1

Abstract

Successful development of effective therapeutic interventions for neurodegenerative diseases will require a deeper understanding of mechanisms of disease initiation and progression. In this respect, an unresolved issue about many neurodegenerative diseases is why neurons are particularly sensitive to defects in ubiquitous cellular processes. One example is Niemann Pick type C1 (NPC1), caused by defects in cholesterol trafficking in all cells, but where neurons are preferentially damaged. Understanding this selective failure is limited by the difficulty of obtaining live human neurons from affected patients. To solve this problem we generated neurons with decreased function of NPC1 from human embryonic stem cells (hESC) and from NPC1 patient specific induced pluripotent stem cells (IPSC), and used them to test the hypothesis that defective cholesterol handling leads to enhanced pathological phenotypes in neurons. We found that human NPC1 neurons have strong spontaneous activation of autophagy, but downstream processing of autophagic intermediates is impaired, which induces accumulation of mitochondrial fragments. We were able to rescue these abnormal phenotypes in NPC1 neurons by inhibiting autophagy, and by mobilization of cholesterol from the lysosomal compartment. Our data highlight the central role that autophagy failure plays in the selective neuronal failure observed in NPC1, and provides the first example of a process that causes preferential neuronal defects in this devastating childhood neurodegenerative disease.