J Alzheimers Dis. 2001 Feb;3(1):121-129. Recent advances in the understanding of the role of synaptic proteins in Alzheimer's Disease and other neurodegenerative disorders.
Masliah E.
Departments of Neurosciences and Pathology University of California San Diego, School of Medicine La Jolla, California 92093, USA.
Synaptic damage is an early pathological event common to many neurodegenerative disorders such as Alzheimer's disease (AD) and is the best correlate to the cognitive impairment. Several molecules involved in AD and in other neurodegenerative disorders play an important role in synaptic function and when misfolded aggregate and form amyloid fibrils. Synaptic proteins with an amyloid domain include amyloid beta-protein precursor, prion protein, huntingtin, ataxin-1 and alpha-synuclein. Two of the possible mechanisms by which alterations in synaptic proteins lead to synapse damage are: 1) misfolded or aggregated synaptic molecules have lost their normal function and/or 2) they have gained a toxic capacity. Recent studies support the possibility that while oligomers are toxic, polymers might be inactive. The mechanisms by which oligomers trigger synapse loss could be related to their ability to triggers stress signals once they enter the nucleus and/or accumulate at the endoplasmic reticulum.
PMID:_12214081 [PubMed - as supplied by publisher]
J Alzheimers Dis. 2000 Mar;2(1):27-35. The Thr183Ala Mutation, Not the Loss of the First Glycosylation Site, Alters the Physical Properties of the Prion Protein.
Capellari S, Zaidi SI, Long AC, Kwon EE, Petersen RB.
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106-2622, USA.
The abnormal form of the prion protein has increased resistance to protease digestion and is insoluble in non-ionic detergents. The normal prion protein is modified by the non-obligatory addition of two N-linked glycans. One pathogenic mutation, Thr to Ala at residue 183 of the human prion protein, blocks addition of the first glycan to the Asp residue 181. This mutation has been reported to result in intracellular retention of the mutant protein and its acquisition of pathogenic properties, presumably due to the lack of the glycan. We report that the lack of the N-linked glycan at residue 181 is not responsible for the block in transport or the acquisition of pathogen-like properties, rather, the Thr to Ala mutation is itself the probable cause of the pathogenic phenotype.
PMID:_12214108 [PubMed - as supplied by publisher]
J Alzheimers Dis. 1999 Dec;1(6):419-424. Decreased Levels of Amyloid-beta 1-42 in Cerebrospinal Fluid of Creutzfeldt-Jakob Disease Patients.
Van Everbroeck B, Green AJ, Pals P, Martin JJ, Cras P.
Laboratory of Neurobiology, Born Bunge Foundation, University of Antwerp, Wilrijk, Belgium.
Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative disease caused by the prion protein. In the search for biochemical markers for CJD, cerebrospinal fluid (CSF) of 101 patients was analysed for 14-3-3 protein, hTau-protein and amyloid-beta 1-42 (Abeta_1-42). The 14-3-3 test had a specificity of 91.5% and a sensitivity of 84%. The hTau test resulted in 95% specificity and 74% sensitivity, when a cut-off of 1530 pg/ml was used. Abeta_1-42 detection in CSF of 29 probable or definite CJD patients revealed significantly decreased values (p=0.01) compared to a group of 22 neurological controls. In the CJD patients a mean of 319+/-102 pg/ml was found. In the neurological control group a mean of 553+/-268 pg/ml was observed. In patients with a false positive 14-3-3 test (n=5) a mean of 716+/-441 pg/ml was found. We conclude that determination of Abeta_1-42 levels in CSF can be useful for identifying false positive 14-3-3 results in suspected CJD patients. We also compared the presence of senile plaques and the Abeta_1-42 levels in CSF of CJD patients. No clear correlation between them was found in this series. This signifies that the deceased Abeta_1-42 levels in CSF are not just due to plaque retention but that other mechanisms must also play a role.
PMID:_12214117 [PubMed - as supplied by publisher]
Curr Protein Pept Sci. 2002 Dec;3(6):643-52. Post-translational modifications in prion proteins.
Otvos L Jr, Cudic M.
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA. skachhsu.edu
Prions are a novel class of infectious pathogens that cause a group of fatal prion diseases in which the benign cellular form of the prion protein (PrP(C)) is transformed into the disease-related scrapie variant (PrP(SC)). The two PrP isoforms differ in their structure and resistance to degradation. The molecular mechanism by which the PrP(SC) is formed and causes infectivity or neurodegeneration is not known. In a compelling and emerging view, post-translational modifications (or the lack thereof) play roles in the transformation of PrP(C) to PrP(SC). Human PrP contains two consensus sites for N-linked glycosylation, at Asn181 and Asn197. From the functional standpoint, glycosylation can modify either the conformation of PrP(C), or the stability of PrP(SC) and, hence, the rate of PrP(SC) clearance. So far the NMR structures of only recombinant, non-glycosylated prions are known, while the structure of the glycosylated form is estimated by molecular modeling. A number of native amino acid mutations in PrP can be mapped near the glycosylation sites. Normal prion protein has been demonstrated to be a copper binding protein, and increasing evidence has shown correlation between the level of PrP expression and tolerance to oxidative stress. Moreover, histochemistry for nitrotyrosine is used for detection of neuronal labeling, a sign of a peroxynitrite-mediated neuronal degradation and a marker for nitrative stress in scrapie-infected mouse brains. It is an intriguing proposition that the post-translational modifications alone, or in combination with amino acid changes, play dominant roles in the pathogenic transformation of PrP(C) to PrP(SC).
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