Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells.
Activated protein C (APC) is a signaling protease with anticoagulant activity. Here, we have used mice expressing a mutation in superoxide dismutase-1 (SOD1) that is linked to amyotrophic lateral sclerosis (ALS) to show that administration of APC or APC analogs with reduced anticoagulant activity after disease onset slows disease progression and extends survival. A proteolytically inactive form of APC with reduced anticoagulant activity provided no benefit. APC crossed the blood-spinal cord barrier in mice via endothelial protein C receptor. When administered after disease onset, APC eliminated leakage of hemoglobin-derived products across the blood-spinal cord barrier and delayed microglial activation. In microvessels, motor neurons, and microglial cells from SOD1-mutant mice and in cultured neuronal cells, APC transcriptionally downregulated SOD1. Inhibition of SOD1 synthesis in neuronal cells by APC required protease-activated receptor-1 (PAR1) and PAR3, which inhibited nuclear transport of the Sp1 transcription factor. Diminished mutant SOD1 synthesis by selective gene excision within endothelial cells did not alter disease progression, which suggests that diminished mutant SOD1 synthesis in other cells, including motor neurons and microglia, caused the APC-mediated slowing of disease. The delayed disease progression in mice after APC administration suggests that this approach may be of benefit to patients with familial, and possibly sporadic, ALS.
Zhong
Zhihui
Z
Center for Neurodegenerative and Vascular Brain Disorders and Department of Neurological Surgery, University of Rochester Medical Center, Rochester, New York 14642, USA.
Ilieva
Hristelina
H
Hallagan
Lee
L
Bell
Robert
R
Singh
Itender
I
Paquette
Nicole
N
Thiyagarajan
Meenakshisundaram
M
Deane
Rashid
R
Fernandez
Jose A
JA
Lane
Steven
S
Zlokovic
Anna B
AB
Liu
Todd
T
Griffin
John H
JH
Chow
Nienwen
N
Castellino
Francis J
FJ
Stojanovic
Konstantin
K
Cleveland
Don W
DW
Zlokovic
Berislav V
BV
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004727:Endothelium / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D008297:Male; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000201:enzymology*; D009046:Motor Neurons / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011486:Protein C / Q000494:pharmacology* / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000378:metabolism; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013116:Spinal Cord / Q000098:blood supply / Q000201:enzymology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D011486:Protein C; D011956:Receptors, Cell Surface; D044462:Receptors, Proteinase-Activated; D016329:Sp1 Transcription Factor; D013482:Superoxide Dismutase