Prion protein and metal interaction: physiological and pathological implications.
Metal induced free radicals are important mediators of neurotoxicity in several neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Similar evidence is now emerging for prion diseases, a group of neurodegenerative disorders of humans and animals. The main pathogenic agent in all prion disorders is PrP-scrapie (PrP(Sc)), a beta-sheet rich isoform of a normal cell surface glycoprotein known as the prion protein (PrP(C)). Deposits of PrP(Sc) in the brain parenchyma are believed to induce neurotoxicity through poorly understood mechanisms. Recent reports suggest that imbalance of brain metal homeostasis is a significant cause of PrP(Sc)-associated neurotoxicity, though the underlying mechanisms are difficult to explain based on existing information. Proposed hypotheses include a functional role for PrP(C) in metal metabolism, and loss of this function due to aggregation to the disease associated PrP(Sc) form as the cause of brain metal imbalance. Other views suggest gain of toxic function by PrP(Sc) due to sequestration of PrP(C)-associated metals within the aggregates, resulting in the generation of redox-active PrP(Sc) complexes. The physiological implications of some PrP(C)-metal interactions are known, while others are still unclear. The pathological implications of PrP(C)-metal interaction include metal-induced oxidative damage, and in some instances conversion of PrP(C) to a PrP(Sc)-like form. Despite its significance, only limited information is available on PrP-metal interaction and its implications on prion disease pathogenesis. In this review, we summarize the physiological significance and pathological implications of PrP-metal interaction on prion disease pathogenesis.
Singh
Neena
N
The Department of Pathology, Case Western Reserve University, 2103, Cornell Road, Cleveland, Ohio 44106, USA. neena.singh@case.edu
Das
Dola
D
Singh
Ajay
A
Mohan
Maradumane L
ML
D000818:Animals; D006801:Humans; D008670:Metals / Q000378:metabolism*; D008954:Models, Biological; D018620:PrPSc Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017096:Prion Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000502:physiology
D008670:Metals; D018620:PrPSc Proteins; D011328:Prions