Mechanisms of Neurodegeneration in Niemann-Pick Type C Disease

Abstract

Lysosomal storage diseases (LSDs) are a heterogeneous group of more than 70 inherited disorders characterized by the accumulation of lysosomal substrates due organellar dysfunction. This accumulation of substrates compromises lysosomal function and leads to a variety secondary effects, including defects in autophagy, calcium homeostasis, oxidative stress and activation of cell death pathways. LSDs manifest in a wide spectrum of clinical phenotypes. Notably, two-thirds of patients across LSDs display significant neurological symptoms. Niemann-Pick C disease (NPC) is an autosomal recessive LSD that primarily affects children and causes severe, progressive neurodegeneration and early death. NPC is caused by mutations in NPC1 or NPC2, proteins that function in concert to export cholesterol from the lysosome; defects in either of these two proteins leads to abnormal cholesterol trafficking and storage within the lysosomal compartment. Although we have increased our understanding of the function of NPC1 and NPC2 in cholesterol trafficking, the mechanisms that underlie neurodegeneration in NPC are not well understood, and there are currently no FDA approved treatments for this disease. This dissertation aims to characterize mechanisms of neurodegeneration in NPC and identify potential targets for therapeutic intervention. In Chapter 1, this thesis outlines LSDs and focuses in on the genetics and pathology of NPC. It discusses what is known about key pathways that contribute to disease pathogenesis, including autophagy, lysosomal membrane permeabilization, and TDP-43 proteinopathy. In Chapter 2, this thesis describes the intersection between altered calcium homeostasis and dysfunctional autophagy in lysosomal diseases. In Chapter 3, this thesis provides primary data demonstrating that NPC cells are more sensitive to lysosomal damage as a consequence of lipid storage. Furthermore, the data presented identify a role for Fbxo2 in CNS lysophagy and establishes its functional importance in NPC. In Chapter 4, this thesis presents primary data that examines the connection between dysfunctional neuron autophagy and TDP-43 proteinopathy in the NPC brain. Furthermore, these data provide the first evidence nuclear pathology in an LSD. Finally, Chapter 5 summarizes these findings and discusses remaining questions and suggests future directions. The work presented in this dissertation seeks to understand mechanisms underlying neurodegeneration in NPC, and I hope that this work will contribute to the identification of novel therapeutic strategies.