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Anatomically defined neuron-based rescue of neurodegenerative Niemann-Pick type C disorder.

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.

Pubmed ID: 21430138


  • Lopez ME
  • Klein AD
  • Dimbil UJ
  • Scott MP


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

March 23, 2011

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM007276
  • Agency: NIGMS NIH HHS, Id: GM07790
  • Agency: NINDS NIH HHS, Id: R01 NS073691
  • Agency: NIGMS NIH HHS, Id: T32 GM007790-33
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Ataxia
  • Blotting, Western
  • Body Weight
  • Cell Count
  • Dystonia
  • Filipin
  • Genes, Reporter
  • Genetic Therapy
  • Genotype
  • Immunohistochemistry
  • Inflammation
  • Mice
  • Mice, Knockout
  • Microglia
  • Nesting Behavior
  • Neurons
  • Niemann-Pick Disease, Type C
  • Proteins
  • Psychomotor Performance
  • Purkinje Fibers
  • Sterols
  • Survival