Kunyan Zhang1, G Angus McQuibban2, Claudia Silva1, Georgina S Butler3, James B Johnston1, Janet Holden4, Ian Clark-Lewis2, 5, Christopher M Overall2, 3
& Christopher Power1, 61
Department of Clinical Neurosciences, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
2
Departments of Biochemistry and Molecular Biology, University of British Columbia, 2199 Westbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
3
Departments of Oral Biological and Medical Sciences, University of British Columbia, 2199 Westbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
4
Department of Pathology, University of British Columbia, 2199 Westbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
5
Department of Biomedical Research Centre, University of British Columbia, 2199 Westbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
6
Department of Microbiology and Infectious Diseases, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
Correspondence should be addressed to Christopher M Overall chris.overall@ubc.ca or Christopher Power power@ucalgary.ca
(SDF-1), a chemokine overexpressed by astrocytes during HIV infection, was converted to a highly neurotoxic protein after precise proteolytic processing by active MMP-2, which removed the N-terminal tetrapeptide. Implantation of cleaved SDF-1(5−67) into the basal ganglia of mice resulted in neuronal death and inflammation with ensuing neurobehavioral deficits that were abrogated by neutralizing antibodies to SDF-1 and an MMP inhibitor drug. Hence, this study identifies a new in vivo neurotoxic pathway in which cleavage of a chemokine by an induced metalloproteinase results in neuronal apoptosis that leads to neurodegeneration.
: amplification by microglia triggers neurotoxicity
