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PMID:16116427

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Citation

Zhao, L, Longo-Guess, C, Harris, BS, Lee, JW and Ackerman, SL (2005) Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP. Nat. Genet. 37:974-9

Abstract

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 uncertain. 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 BiP, a crucial ER chaperone. These findings provide evidence that perturbation of ER chaperone function in terminally differentiated neurons leads to protein accumulation, ER stress and subsequent neurodegeneration.

Links

PubMed Online version:10.1038/ng1620

Keywords

Animals; Ataxia/etiology; Autoantigens/metabolism; Cell Nucleus/metabolism; Cerebellum/pathology; Endoplasmic Reticulum; Female; Guanine Nucleotide Exchange Factors/physiology; Heat-Shock Proteins/genetics; Heat-Shock Proteins/physiology; Homozygote; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Chaperones/genetics; Molecular Chaperones/physiology; Molecular Sequence Data; Mutation; Nerve Degeneration; Purkinje Cells/metabolism; Purkinje Cells/pathology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SIL1

located_in

GO:0005783: endoplasmic reticulum

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SIL1

part_of

GO:0005783: endoplasmic reticulum

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000121)

Seeded From UniProt

complete


See also

References

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