Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP.
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.
Zhao
Lihong
L
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
Longo-Guess
Chantal
C
Harris
Belinda S
BS
Lee
Jeong-Woong
JW
Ackerman
Susan L
SL
D000818:Animals; D001259:Ataxia / Q000209:etiology; D001324:Autoantigens / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002531:Cerebellum / Q000473:pathology; D004721:Endoplasmic Reticulum; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation; D009410:Nerve Degeneration; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology
D001324:Autoantigens; D000091342:Endoplasmic Reticulum Chaperone BiP; D020662:Guanine Nucleotide Exchange Factors; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones