Prion protein fragment (106-126) induces prothrombotic state by raising platelet intracellular calcium and microparticle release.
Prion diseases are neurodegenerative disorders where infectious prion proteins (PrP) accumulate in brain leading to aggregation of amyloid fibrils and neuronal cell death. The amino acid sequence 106-126 from prion proteins, PrP(106-126), is highly amyloidogenic and implicated in prion-induced pathologies. As PrP is known to be expressed in blood following leakage from brain tissue, we sought to investigate its biological effects on human platelets, which have been widely employed as 'peripheral' model for neurons. Our findings suggested that, PrP(106-126) (20μM) induced dramatic 30-fold rise in intracellular calcium (from 105±30 to 3425±525nM) in platelets, which was attributable to influx from extracellular fluid with comparatively less contribution from intracellular stores. Calcium mobilization was associated with 8-10-fold stimulation in the activity of thiol protease calpain that led to partial cleavage of cytoskeleton-associated protein talin and extensive shedding of microparticles from platelets, thus transforming platelets to 'activated' phenotype. Both proteolysis of talin and microparticle release were precluded by calpeptin, a specific inhibitor of calpain. As microparticles are endowed with phosphatidylserine-enriched surface and hence are pro-coagulant in nature, exposure to prion favored a thrombogenic state in the organism.
Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India.
Ram L
RL
Mallick
Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India.
Sharda
S
Kumari
Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India.
Nitesh
N
Singh
Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India.
Vijay K
VK
Sonkar
Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India. Electronic address: ddash.biochem@gmail.com.
Debabrata
D
Dash
D001777:Blood Coagulation; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002154:Calpain / Q000037:antagonists & inhibitors; D055252:Cell-Derived Microparticles / Q000378:metabolism; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D015539:Platelet Activation / Q000187:drug effects; D017096:Prion Diseases / Q000097:blood* / Q000150:complications; D011328:Prions / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D016608:Talin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood* / Q000209:etiology
D004151:Dipeptides; D010446:Peptide Fragments; D011328:Prions; D016608:Talin; C082632:prion protein (106-126); C071482:calpeptin; D002154:Calpain; D002118:Calcium
Calpain; Intracellular calcium; Microparticles; Platelets; Prion