Human Molecular Genetics Advance Access published online on December 12, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn423
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Tau deletion exacerbates the phenotype of Niemann-Pick type C mice and implicates autophagy in pathogenesis
1 Neuroscience Program, The University of Michigan Medical School, Ann Arbor, Michigan 48109 2 Medical Scientist Training Program, The University of Michigan Medical School, Ann Arbor, Michigan 48109 3 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 September 22, 2008; Revised December 9, 2008; Accepted December 9, 2008
Hyperphosphorylation and aggregation of the microtubule binding protein tau characterizes a diverse array of neurodegenerative disorders. Most of these lack mutations in the encoding MAPT gene, and the role of tau in disease pathogenesis remains controversial. Among these tauopathies is Niemann-Pick type C disease, a lysosomal storage disorder characterized by progressive neurodegeneration and premature death, most often caused by an inherited deficiency in the intracellular lipid trafficking protein NPC1. To determine the extent to which tau affects Niemann-Pick type C disease pathogenesis, we generated Npc1 –/– mice deficient in tau. Unexpectedly, NPC1/tau double null mutants are generated in markedly smaller litters, exhibit an enhanced systemic phenotype, and die significantly earlier than NPC1 single null mutants. As autophagy is up-regulated in Niemann-Pick type C disease, and protein degradation through this pathway depends upon movement along microtubules, we knocked down MAPT expression in NPC1-deficient human fibroblasts and examined effects on this pathway. We show that an acute reduction of tau expression in a cellular model of Niemann-Pick type C disease decreases induction and flux through the autophagic pathway. Our data establish that MAPT deletion exacerbates the Niemann-Pick type C disease phenotype through a mechanism independent of tau protein aggregation, and identifies a critical role for tau in the regulation of autophagy in NPC1 deficient cells.
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