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Truncated forms of the human prion protein in normal brain and in prion diseases
S G Chen1, D B Teplow, P Parchi
1Division of Neuropathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Abstract:
The cellular form of the prion protein (PrPc) is a glycoprotein anchored to the cell membrane by a glycosylphosphatidylinositol moiety. An aberrant form of PrPc that is partially resistant to proteases, PrPres, is a hallmark of prion diseases, which in humans include Cruetzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia. We have characterized the major forms of PrP in normal and pathological human brains. A COOH-terminal fragment of PrPc, designated C1, is abundant in normal and CJD brains as well as in human neuroblastoma cells. Sequence analysis revealed that C1 contains alternative NH2 termini starting at His-111 or Met-112. Like PrPc, C1 is glycosylated, anchored to the cell membrane, and is heat-stable. Consistent with the lack of the NH2-terminal region of PrPc, C1 is more acidic than PrPc and does not bind heparin. An additional fragment longer than C1, designated C2, is present in substantial amounts in CJD brains. Like PrPres, C2 is resistant to proteases and is detergent-insoluble. Our data indicate that C1 is a major product of normal PrPc metabolism, generated by a cleavage that disrupts the neurotoxic and amyloidogenic region of PrP comprising residues 106-126. This region remains intact in C2, suggesting a role for C2 in prion diseases.
Insights
Researchers identified two key fragments of the prion protein (PrP) in human brains. Fragment C1 is a normal metabolic product, while C2 may play a role in prion diseases like Creutzfeldt-Jakob disease (CJD).
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- The cellular prion protein (PrPc) is a membrane-anchored glycoprotein.
- Prion diseases, including Creutzfeldt-Jakob disease (CJD), are characterized by an abnormal, protease-resistant form (PrPres).
Purpose of the Study:
- To characterize major prion protein (PrP) forms in normal and pathological human brains.
- To investigate the metabolic products of PrPc and their potential roles in prion diseases.
Main Methods:
- Protease resistance assays
- Sequence analysis of PrP fragments
- Biochemical characterization of PrP fragments (glycosylation, membrane anchoring, heat stability, acidity, heparin binding, detergent solubility)
Main Results:
- A COOH-terminal fragment, C1, is abundant in normal and CJD brains and is a major product of normal PrPc metabolism.
- C1 results from a cleavage that removes the neurotoxic/amyloidogenic PrP region (residues 106-126).
- A longer fragment, C2, found in CJD brains, is protease-resistant and detergent-insoluble, with the 106-126 region intact.
Conclusions:
- C1 represents a normal metabolic product of PrPc, generated by cleavage within the potentially toxic region.
- C2, retaining the 106-126 region, is associated with CJD and may be involved in prion pathogenesis.