Document Detail


Conditional Niemann-Pick C mice demonstrate cell autonomous Purkinje cell neurodegeneration.
MedLine Citation:
PMID:  20007718     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Pathways regulating neuronal vulnerability are poorly understood, yet are central to identifying therapeutic targets for degenerative neurological diseases. Here, we characterize mechanisms underlying neurodegeneration in Niemann-Pick type C (NPC) disease, a lysosomal storage disorder characterized by impaired cholesterol trafficking. To date, the relative contributions of neuronal and glial defects to neuron loss are poorly defined. Using gene targeting, we generate Npc1 conditional null mutant mice. Deletion of Npc1 in mature cerebellar Purkinje cells leads to an age-dependent impairment in motor tasks, including rotarod and balance beam performance. Surprisingly, these mice did not show the early death or weight loss that are characteristic of global Npc1 null mice, suggesting that Purkinje cell degeneration does not underlie these phenotypes. Histological examination revealed the progressive loss of Purkinje cells in an anterior-to-posterior gradient. This cell autonomous neurodegeneration occurs in a spatiotemporal pattern similar to that of global knockout mice. A subpopulation of Purkinje cells in the posterior cerebellum exhibits marked resistance to cell death despite Npc1 deletion. To explore this selective response, we investigated the electrophysiological properties of vulnerable and susceptible Purkinje cell subpopulations. Unexpectedly, Purkinje cells in both subpopulations displayed no electrophysiological abnormalities prior to degeneration. Our data establish that Npc1 deficiency leads to cell autonomous, selective neurodegeneration and suggest that the ataxic symptoms of NPC disease arise from Purkinje cell death rather than cellular dysfunction.
Authors:
Matthew J Elrick; Chris D Pacheco; Ting Yu; Nahid Dadgar; Vikram G Shakkottai; Christopher Ware; Henry L Paulson; Andrew P Lieberman
Related Documents :
2331788 - Purkinje cell loss is due to a direct action of the weaver gene in purkinje cells: evid...
16079458 - Decreased distribution of nitric oxide synthase and vasoactive intestinal polypeptide p...
6995358 - Biochemical alteration in cells following phagocytosis of m. leprae--the consequence--a...
15265898 - Cross-reactive tcr responses to self antigens presented by different mhc class ii molec...
19001878 - Parp-1 is involved in autophagy induced by dna damage.
23935528 - Integrative modeling of eqtls and cis-regulatory elements suggests mechanisms underlyin...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-12-10
Journal Detail:
Title:  Human molecular genetics     Volume:  19     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-02-05     Completed Date:  2010-06-29     Revised Date:  2011-07-25    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  837-47     Citation Subset:  IM    
Affiliation:
Department of Pathology, University of Michigan, Ann Arbor, MI 48109-0605, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Cell Survival
Disease Models, Animal
Mice
Mice, Transgenic
Nerve Degeneration
Neurons / metabolism*
Niemann-Pick Disease, Type C / metabolism,  pathology*
Proteins / genetics*,  metabolism
Purkinje Cells / pathology*
Grant Support
ID/Acronym/Agency:
F31 NS51143/NS/NINDS NIH HHS; R01 NS063967/NS/NINDS NIH HHS; R03 NS057150/NS/NINDS NIH HHS; T32 GM07863/GM/NIGMS NIH HHS; T32 MH014279/MH/NIMH NIH HHS
Chemical
Reg. No./Substance:
0/Npc1 protein, mouse; 0/Proteins
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Molecular characterization of the interaction of staphylococcal microbial surface components recogni...
Next Document:  Tuberculous endocarditis: valvular and right atrial involvement.