Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP

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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.

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Figure 1: Purkinje neuron degeneration in the woozy mutant cerebellum.
Figure 2: Identification of Sil1 as the wz locus.
Figure 3: The wz mutation results in formation of protein accumulations in Purkinje cells.
Figure 4: Localization of protein accumulations in Purkinje cells.
Figure 5: Truncation of Sil1 induces the ER stress response.
Figure 6: ER stress response in wz Purkinje cells.

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We thank The Jackson Laboratory sequencing facility, histology, microinjection and bioimaging services for their contributions; R. Bronson for assistance with electron microscopy; and L.L. Beverly-Staggs for technical assistance. We also thank BayGenomics, which is supported by the US National Heart, Lung, and Blood Institute. This study is supported by grants from the US National Institutes of Health (S.L.A) and a Mouse Mutant Resource grant from the US National Institutes of Health.

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Correspondence to Susan L Ackerman.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Co-localization of SIL1 and BiP. (PDF 850 kb)

Supplementary Fig. 2

SIL1 truncated by the wz mutation retains the ability to interact with BiP. (PDF 163 kb)

Supplementary Table 1

Primers used in Sil1 genomic and RT-PCR. (PDF 27 kb)

Supplementary Video 1

A four-month old CxB5/ByJ-woozy mutant mouse (wz/wz) and its wild type littermate (+/+) are shown. Note the tremors and truncal ataxia in the wz/wz mouse. (MOV 1368 kb)

Supplementary Methods (PDF 34 kb)

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Zhao, L., Longo-Guess, C., Harris, B. et al. Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP. Nat Genet 37, 974–979 (2005) doi:10.1038/ng1620

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