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Journal of Virology, January 2000, p. 411-417, Vol. 74, No. 1
0022-538X/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Upregulation of the Genes Encoding Lysosomal Hydrolases, a Perforin-Like Protein, and Peroxidases in the Brains of Mice Affected with an Experimental Prion Disease

Juraj Kopacek,1,2,dagger Suehiro Sakaguchi,1 Kazuto Shigematsu,3 Noriyuki Nishida,1 Ryuichirou Atarashi,1 Ryota Nakaoke,1 Ryozo Moriuchi,1 Masami Niwa,2 and Shigeru Katamine1,*

The Departments of Bacteriology,1 Pathology,3 and Pharmacology,2 Nagasaki University School of Medicine, Nagasaki 852-8523, Japan

Received 23 June 1999/Accepted 16 September 1999

In an attempt to identify the molecules involved in the pathogenesis of prion diseases, we performed cDNA subtraction on the brain tissues of mice affected with an experimental prion disease and the unaffected control. The genes identified as being upregulated in the prion-affected brain tissue included those encoding a series of lysosomal hydrolases (lysozyme M and both isoforms of beta -N-acetylhexosaminidase), a perforin-like protein (macrophage proliferation-specific gene-1 [MPS-1]), and an oxygen radical scavenger (peroxiredoxin). Dramatic increases in the expression level occurred at between 12 and 16 weeks after intracerebral inoculation of the prion, coinciding with the onset of spongiform degeneration. The proteinase K-resistant prion protein (PrPSc) became detectable by immunoblotting well before 12 weeks, suggesting a causal relationship between this and the gene activation. Immunohistochemistry paired with in situ hybridization on sections of the affected brain tissue revealed that expression of the peroxiredoxin gene was detectable only in astrocytes and was noted throughout the affected brain tissue. On the other hand, the genes for the lysosomal hydrolases and MPS-1 were overexpressed exclusively by microglia, which colocalized with the spongiform morphological changes. A crucial role for microglia in the spongiform degeneration by their production of neurotoxic substances, and possibly via the aberrant activation of the lysosomal system, would have to be considered.

* Corresponding author. Mailing address: Department of Bacteriology, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. Phone: 81-95-849-7057. Fax: 81-95-849-7060. E-mail: katamine{at}net.nagasaki-u.ac.jp.

dagger Present address: Department of Molecular Biology and Morphogenesis of Viruses, Institute of Virology, Slovak Academy of Sciences, 842 46 Bratislava, Slovakia.

Journal of Virology, January 2000, p. 411-417, Vol. 74, No. 1
0022-538X/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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