Role of Erk1/2 activation in prion disease pathogenesis: absence of CCR1 leads to increased Erk1/2 activation and accelerated disease progression.
Prion diseases are neurodegenerative infections with gliosis and vacuolation. The mechanisms of degeneration remain unclear, but chemokines may be important. In current experiments CCR1 knock-out (KO) mice succumbed more rapidly to scrapie infection than WT controls. Infected KO mice had upregulation of CCL3, a CCR1 ligand, and CCR5, a receptor with specificity for CCL3. Both infected KO and WT mice had upregulation of CCR5-mediated signaling involving activation of Erk1/2 in astrocytes; however, activation was earlier in KO mice suggesting a role in pathogenesis. In both mouse strains activation of the Erk1/2 pathway may lead to astrocyte dysfunction resulting in neurodegeneration.
LaCasse
Rachel A
RA
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South 4th Street, Hamilton, MT 59840, United States.
Striebel
James F
JF
Favara
Cynthia
C
Kercher
Lisa
L
Chesebro
Bruce
B
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D018620:PrPSc Proteins / Q000276:immunology* / Q000378:metabolism; D017096:Prion Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D054389:Receptors, CCR1 / Q000172:deficiency*; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism
C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; C515301:Ccr1 protein, mouse; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D018620:PrPSc Proteins; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D048052:Mitogen-Activated Protein Kinase 3