Human Molecular Genetics Advance Access published online on April 27, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm100
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Autophagy in Niemann-Pick C disease is dependent upon Beclin-1 and responsive to lipid trafficking defects
1 Neuroscience Program, The University of Michigan Medical School, Ann Arbor, Michigan 48109 2 Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan 48109
* Address correspondence to: Andrew Lieberman, Department of Pathology, University of Michigan Medical School, 3510 MSRB1, 1150 W. Medical Center Dr., Ann Arbor, Michigan 48109. Telephone: (734) 647-4624, Fax: (734) 615-3441, Email: liebermn{at}umich.edu
Received February 7, 2007; Revised April 11, 2007; Accepted April 11, 2007
Niemann-Pick C disease is an autosomal recessive lipid storage disorder characterized by a disruption of sphingolipid and cholesterol trafficking that produces cognitive impairment, ataxia and death, often in childhood. Most cases are caused by loss of function mutations in the Npc1 gene, which encodes a protein that localizes to late endosomes and functions in lipid sorting and vesicle trafficking. Here we demonstrate that NPC1 deficient primary human fibroblasts, like npc1-/- mice, showed increased autophagy as evidenced by elevated LC3-II levels, numerous autophagic vacuoles and enhanced degradation of long-lived proteins. Autophagy due to NPC1 deficiency was associated with increased expression of Beclin-1 rather than activation of the Akt-mTOR-p70 S6K signaling pathway, and siRNA knockdown of Beclin-1 decreased long-lived protein degradation. Induction of cholesterol trafficking defects in wild type fibroblasts by treatment with U18666A increased Beclin-1 and LC3-II expression, while treatment of NPC1 deficient fibroblasts with the sphingolipid-lowering compound NB-DGJ failed to alter the expression of either Beclin-1 or LC3-II. Primary fibroblasts from patients with two other sphingolipid storage diseases characterized by sphingolipid trafficking defects, NPC2 deficiency and Sandhoff disease, also showed elevated Beclin-1 and LC3-II levels. In contrast, Gaucher disease fibroblasts, which traffic sphingolipids normally, showed wild type levels of Beclin-1 and LC3-II. Our data define a critical role for Beclin-1 in the activation of autophagy due to NPC1 deficiency, and reveal an unexpected role for lipid trafficking in the regulation of this pathway in patients with several sphingolipid storage diseases.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. L. Cianciola and C. R. Carlin Adenovirus RID-{alpha} activates an autonomous cholesterol regulatory mechanism that rescues defects linked to Niemann-Pick disease type C J. Cell Biol., November 16, 2009; 187(4): 537 - 552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Puertollano and K. Kiselyov TRPMLs: in sickness and in health Am J Physiol Renal Physiol, June 1, 2009; 296(6): F1245 - F1254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Pacheco, M. J. Elrick, and A. P. Lieberman Tau deletion exacerbates the phenotype of Niemann-Pick type C mice and implicates autophagy in pathogenesis Hum. Mol. Genet., March 1, 2009; 18(5): 956 - 965. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Cornell, M. Aarts, D. Bautista, J. Garcia-Anoveros, K. Kiselyov, and E. R. Liman A Double TRPtych: Six Views of Transient Receptor Potential Channels in Disease and Health J. Neurosci., November 12, 2008; 28(46): 11778 - 11784. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Alvarez, A. Klein, J. Castro, G. I. Cancino, J. Amigo, M. Mosqueira, L. M. Vargas, L. F. Yevenes, F. C. Bronfman, and S. Zanlungo Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease FASEB J, October 1, 2008; 22(10): 3617 - 3627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vergarajauregui, P. S. Connelly, M. P. Daniels, and R. Puertollano Autophagic dysfunction in mucolipidosis type IV patients Hum. Mol. Genet., September 1, 2008; 17(17): 2723 - 2737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Phillips, E. A. Woodruff III, P. Liang, M. Patten, and K. Broadie Neuronal Loss of Drosophila NPC1a Causes Cholesterol Aggregation and Age-Progressive Neurodegeneration J. Neurosci., June 25, 2008; 28(26): 6569 - 6582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Settembre, A. Fraldi, L. Jahreiss, C. Spampanato, C. Venturi, D. Medina, R. de Pablo, C. Tacchetti, D. C. Rubinsztein, and A. Ballabio A block of autophagy in lysosomal storage disorders Hum. Mol. Genet., January 1, 2008; 17(1): 119 - 129. [Abstract] [Full Text] [PDF]
|
|