Ceruloplasmin Deamidation in Neurodegeneration: From Loss to Gain of Function

Abstract

Neurodegenerative disorders can induce modifications of several proteins; one of which is ceruloplasmin (Cp), a ferroxidase enzyme found modified in the cerebrospinal fluid (CSF) of neurodegenerative diseases patients. Cp modifications are caused by the oxidation induced by the pathological environment and are usually associated with activity loss. Together with oxidation, deamidation of Cp was found in the CSF from Alzheimer’s and Parkinson’s disease patients. Protein deamidation is a process characterized by asparagine residues conversion in either aspartate or isoaspartate, depending on protein sequence/structure and cellular environment. Cp deamidation occurs at two Asparagine-Glycine-Arginine (NGR)-motifs which, once deamidated to isoAspartate-Glycine-Arginine (isoDGR), bind integrins, a family of receptors mediating cell adhesion. Therefore, on the one hand, Cp modifications lead to loss of enzymatic activity, while on the other hand, these alterations confer gain of function to Cp. In fact, deamidated Cp binds to integrins and triggers intracellular signaling on choroid plexus epithelial cells, changing cell functioning. Working in concert with the oxidative environment, Cp deamidation could reach different target cells in the brain, altering their physiology and causing detrimental effects, which might contribute to the pathological mechanism.

Human blood plasma proteins modeling and binding affinities with Δ9-tetrahydrocannabinol active metabolites: In silico approach

“…The Ceruloplasmin (CP) belongs to oxidase family and copper enzyme present in serum [39]. In neurodegenerative diseases such as Parkinson’s and Alzheimer’s, CP was found in Cerebrospinal fluid (CSF) with modified structure and state [40]. Like APOD, CP has also neuroprotective role [41].…”

Urinary and Plasma Antioxidants in Behavioral Symptoms of Individuals With Autism Spectrum Disorder

“…Reduced plasma Cp levels may induce or be a consequence of neurodegeneration, such as Alzheimer's disease, while decreased plasma SOD activity may exacerbate defective Cp activity, indicating an intrinsic relationship between plasma Cp and SOD levels (86). Elevated serum Cp levels have been associated with impulsiveness in patients with Parkinson's disease (87). Cerebrospinal fluid Cp can be induced in neurodegenerative disorders (88).…”

Ferroptosis in Glaucoma: A Promising Avenue for Therapy

“…[46] Furthermore, variations in ferroptosis-related gene expressions, such as transferrin and inflammatory markers, and downstream expression of ceruloplasmin (CP) and other immune-related proteins, indicate changes in stress state. [54,55] Therefore, understanding glaucoma fundamentally involves linking neural damage to iron-based inflammatory stress, with mitochondria playing a pivotal role.…”

“…This affects the stress state and alters iron movement through allosteric effects. [ 54 ] Research on experimental glaucomatous injury in monkey models revealed significant differences in transferrin and CP mRNA concentrations between moderate or severe unilateral defect groups and normal groups, with increased levels observed in the injured groups. [ 55 ] Here, CP, as a product of iron‐regulating genes, acts as an antioxidant to mitigate damage caused by metal‐induced radicals.…”