Anatomically Defined Neuron-Based Rescue of Neurodegenerative Niemann–Pick Type C Disorder

Abstract

Niemann-Pick type C disease is a fatal lysosomal storage disorder caused by loss of NPC1 function. The disorder severely affects multiple body systems, particularly the nervous system. To test whether rescue of NPC1 activity in neurons, astrocytes, or other cell types can correct the neurological defects, a Tet-inducible Npc1-YFP transgene was introduced into Npc1−/− mice for the cell type-specific rescue of NPC1 loss. NPC1-YFP produced in neurons prevented neuron degeneration, slowed reactive glial activity, and ameliorated the disease. NPC1-YFP produced in astrocytes or in cells of visceral tissue did not. These results suggest that loss of NPC1 activity from neurons is the primary cause of the neuropathology and that rescue of NPC1 function in neurons is sufficient to mitigate the disease. The ability of neurons to survive and function in a cell-autonomous fashion allowed the use of this newly engineered rescue system to further define the brain regions or neuron populations required to ameliorate a neurological symptom. NPC1-YFP produced specifically in cerebellar Purkinje neurons reduced ataxia, increased weight, and prolonged life, but it did not prevent the eventual decline and premature death of Npc1−/− mice. Significant increase in lifespan correlated with sustained reduction of inflammation in the thalamus. Neuron rescue of other forebrain areas provided little benefit. Future work targeting increasingly discrete neuronal networks should reveal which CNS areas are critical for survival. This work may have broad implications for understanding the anatomical and cellular basis of neurological signs and symptoms of other neurodegenerative and lysosomal disorders.

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

“…The phenotype of these mice is similar to, but slightly less severe than, that of Npc1 Ϫ / Ϫ mice ( 26,75 ). More recently, NPC1 was eliminated specifi cally in certain cell types ( 76 ) and, reciprocally, was expressed only in specifi c cells of Npc1 Ϫ / Ϫ mice ( 77 ). These studies have been particularly useful for understanding in which cells of the brain loss of NPC function is the most detrimental (see Loss of NPC Function in Cells of the Brain).…”

“…Furthermore, genetic deletion of NPC1 in astrocytes alone did not cause the neuropathology exhibited by Npc1 Ϫ / Ϫ mice ( 141 ). Nor did Tet-induced expression of NPC1 in astrocytes alone of Npc1 Ϫ / Ϫ mice slow disease progression, except for a small delay in weight loss ( 77 ). In contrast, one study reported that cholesterol storage was decreased, and survival of Npc1 Ϫ / Ϫ mice was increased, by expression of NPC1 in astrocytes under control of the glial fi brillary acidic protein promoter.…”

“…More specifi cally, expression of NPC1 in cerebellar Purkinje neurons (the neurons most affected in NPC disease), but not in neurons of other forebrain areas, of Npc1 Ϫ / Ϫ mice markedly extended life span and lessened the ataxia ( 77 ). In addition, elimination of NPC1 specifi cally in Purkinje neurons caused ataxia and loss of Purkinje cells in an anterior-to-posterior gradient, but, surprisingly, these mice did not exhibit weight loss or premature death ( 76 ).…”

“…For example, when NPC1 was eliminated only in neurons of mice, neuropathology developed typical of that in mice in which NPC1 was eliminated globally ( 141 ). Moreover, expression of NPC1 only in neurons of Npc1 Ϫ / Ϫ mice prevented the neurodegeneration ( 77 ). In addition, in microglianeuron cocultures, the presence of activated Npc1 Ϫ / Ϫ microglia did not cause neuron death ( 135 ).…”

Subcortical Volumetric Reductions in Adult Niemann-Pick Disease Type C: A Cross-Sectional Study

“…18 In murine NPC models, intracellular storage of gangliosides occurs maximally in large pyramidal neurons, Purkinje cells in the cerebellum, and neurons in the lateral thalamus, hippocampus, and brain stem 6,19 ; and maximal neuronal loss occurs in the thalamus and cerebellum. [19][20][21] The earliest human neuropathologic studies showed that neuroaxonal dystrophy was maximal in the thalamus and cerebellum. 22 In humans, neuropathologic studies demonstrated that noncerebellar brain regions develop NFTs in the basal ganglia, thalamus, brain stem, cerebral cortex, and hippocampus.…”