Nature Genetics
37, 974 - 979 (2005)
Published online: 14 August 2005; | doi:10.1038/ng1620
Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiPLihong Zhao1, Chantal Longo-Guess1, Belinda S Harris1, Jeong-Woong Lee1
& Susan L Ackerman1, 21
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA. 2
The Howard Hughes Medical Institute, Bar Harbor, Maine 04609, USA.
Correspondence should be addressed to Susan L Ackerman susan.ackerman@jax.org Endoplasmic reticulum (ER) chaperones and ER stress have been implicated in the pathogenesis of neurodegenerative disorders, such as Alzheimer and Parkinson diseases, but their contribution to neuron death remains uncertain1,
2. In this study, we establish a direct in vivo link between ER dysfunction and neurodegeneration. Mice homozygous with respect to the woozy (wz) mutation develop adult-onset ataxia with cerebellar Purkinje cell loss. Affected cells have intracellular protein accumulations reminiscent of protein inclusions in both the ER and the nucleus. In addition, upregulation of the unfolded protein response, suggestive of ER stress, occurs in mutant Purkinje cells. We report that the wz mutation disrupts the gene Sil1 that encodes an adenine nucleotide exchange factor of BiP3, a crucial ER chaperone4. These findings provide evidence that perturbation of ER chaperone function in terminally differentiated neurons leads to protein accumulation, ER stress and subsequent neurodegeneration.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
