Functional relevance of ceruloplasmin mutations in Parkinson's Disease

Abstract

Increased iron levels of the substantia nigra and the discovery of ceruloplasmin mutations in patients with Parkinson's disease (PD) imply impaired iron metabolism in this neurodegenerative disorder. Ceruloplasmin has ferroxidase activity oxidizing iron(II) to iron(III). In the present study, we analyzed the amount of ceruloplasmin, iron, ferritin, and transferrin and the ceruloplasmin ferroxidase activity in serum of patients with the diagnosis of PD carrying the ceruloplasmin mutations I63T, D544E, and R793H. The impact of these missense mutations on the biosynthesis of holo-ceruloplasmin was investigated in cell culture experiments. Functional relevance was found for the ceruloplasmin mutations I63T and D544E. In vivo, the I63T mutation resulted in half the normal ceruloplasmin concentration and markedly reduced ferroxidase activity in serum from a heteroallelic PD patient. In cell culture, the I63T glycosylphosphatidylinositol (GPI)-linked ceruloplasmin isoform was retained in the endoplasmatic reticulum of human embryonic kidney cells. Furthermore, the D544E polymorphism resulted in significantly reduced serum ceruloplasmin levels and ferroxidase activity in heteroallelic patients and in expression of mainly apo-ceruloplasmin in cell culture. Our studies indicate that altered activity of ceruloplasmin may present a vulnerability factor for iron induced oxidative stress in PD.

Features of ceruloplasmin in the cerebrospinal fluid of Alzheimer’s disease patients

“…In addition, it has recently been reported that mutations of CP are associated with Parkinson's disease (Hochstrasser et al 2005), thus reinforcing the concept that a lower CP activity is associated with neurodegeneration.…”

Lower serum ceruloplasmin levels correlate with younger age of onset in Parkinson’s disease

“…Further evidence for the role of ceruloplasmin in PD comes from a study of 176 PD patients, which detected novel ceruloplasmin gene mutations, some associated with PD [2,21]. This study used transcranial ultrasound to detect hyperechogenicity in the substantia nigra as a marker of increased iron.…”

Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications

“…In HEK293 cells, the I63T GPI-linked isoform of Cp remained in the endoplasmic reticulum. The D544E Cp was expressed at lower levels and exhibited decreased ferroxidase activity (135). Decreased expression of Cp and deficient ferroxidase activity may result in "free iron" accumulation and decreased antioxidant potential.…”