Search

Prion diseases, a group of neurodegenerative disorders affecting humans and animals, have received considerable attention largely because of their intriguing pathogenetic mechanism and the threat they pose to public health [...]

Introduction: Tumor necrosis factor (TNF) inhibitors are widely used to treat rheumatoid arthritis (RA) and their potential to retard Alzheimer's disease (AD) progression has been reported. However, their long‐term effects on the dementia/AD risk remain unknown. Methods: A propensity scored matched retrospective cohort study was conducted among 40,207 patients with RA within the US Veterans Affairs health‐care system from 2000 to 2020. Results: A total of 2510 patients with RA prescribed TNF inhibitors were 1:2 matched to control patients. TNF inhibitor use was associated with reduced dementia risk (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.52–0.80), which was consistent as the study period increased from 5 to 20 years after RA diagnosis. TNF inhibitor use also showed a long‐term effect in reducing the risk of AD (HR: 0.57, 95% CI: 0.39–0.83) during the 20 years of follow‐up. Conclusion: TNF inhibitor use is associated with lower long‐term risk of dementia/AD among US veterans with RA. [ABSTRACT FROM AUTHOR]

Research has been conducted on amadoriases I and II, Aspergillus sp. deglycation isoenzymes. The effect of arginine residues on amadoriase II binding site has been investigated via the use of arginine modification reagent p-hydroxyphenylglyoxal and the results are reported.

Escherichia coli expressed human recombinant doppel protein domain is an alpha-helical protein with 40% helical content. The domain protein is soluble, proteinase K sensitive, and undergoes reversible cooperative thermal denaturation suggesting that it is similar to the newly recognized prion protein.

Research has been conducted on the amadoriase cloning. Aspergillus fumigatus cDNA library preparation and clone isolation by means of the amplified by polymerase chain reaction probe are examined.

Research has been conducted on the transition mechanism between the normal and pathological isoforms of prion protein. Characterization of the biophysical properties of the recombinant protein is discussed.

Abstract Lewy bodies and Lewy neurites constitute the cardinal neuropathological features of both Parkinson's disease (PD) and Lewy body dementia (LBD). Whereas α-synuclein has been found to be the major component of the Lewy body, the mechanisms by which neurons degenerate, as well as basic mechanisms involved in the formation of α-synuclein-related inclusions, remain obscure. We have suggested previously that potential mechanisms are likely to leave a "molecular signature" or protein adduct within the Lewy body, and have found examples of such signatures in previous studies. In this study, we demonstrate increased FOXO3 in association with Lewy bodies and Lewy neurites in LBD and PD brain tissue. Since FOXO proteins are involved in several pathways responsible for the regulation of cell death, cell proliferation, and cell metabolism, the ectopic localization of FOXO3 to Lewy bodies provides evidence that aberrations in basic cellular biochemistry may contribute to inclusion formation, which is likely more complex than a simple "gain of function" toxicity as is commonly opined. In light of the known interaction of FOXO3 and 14-3-3, basic protein-protein interaction between these proteins and α-synuclein may be key.

Abstract Background Mutations in LRRK2 encoding leucine-rich repeat kinase 2 are thus far the most frequent genetic cause associated with autosomal dominant and idiopathic Parkinson's disease (PD). To examine whether LRRK2 is directly associated with neuropathology of PD and other related disorders, we analyzed LRRK2 in brains of patients affected by PD and dementia with Lewy bodies (DLB) using highly specific antibodies to LRRK2. Results We demonstrated that anti-LRRK2 antibodies strongly labelled brainstem and cortical Lewy bodies, the pathological hallmarks of PD and DLB, respectively. In addition, anti-LRRK2 also labelled brain vasculature, axons, and neuronal cell bodies. Interestingly, the immunocytochemical profile of LRRK2 varied with different antibodies depending upon specific antigenic sites along the LRRK2 protein. All anti-LRRK2 antibodies tested that were raised against various regions of LRRK2, were found to be immunoreactive to recombinant LRRK2 on Western blots. However, only the antibodies raised against the N-terminal and C-terminal regions of LRRK2, but not the regions containing folded protein domains, were positive in immunolabeling of Lewy bodies, suggesting a differential exposure of specific antigenic sites of LRRK2 on tissue sections. Conclusion We conclude that LRRK2 is a component of Lewy bodies in both PD and DLB, and therefore plays an important role in the Lewy body formation and disease pathogenesis. Information on the cellular localization of LRRK2 under normal and pathological conditions will deepen our understanding of its functions and molecular pathways relevant to the progression of PD and related disorders.

Prion diseases are characterized by the presence of the abnormal prion protein Pr[P.sup.Sc], which is believed to be generated by the conversion of the [Alpha]-helical structure that predominates in the normal PrP isoform into a [Beta]-sheet structure resistant to proteinase K (PK). In human prion diseases, two major types of Pr[P.sup.Sc], type 1 and 2, can be distinguished based on the difference in electrophoretic migration of the PK-resistant core fragment. In this study, protein sequencing was used to identify the PK cleavage sites of Pr[P.sup.Sc] in 36 cases of prion diseases. We demonstrated two primary cleavage sites at residue 82 and residue 97 for type 1 and type 2 Pr[P.sup.Sc], respectively, and numerous secondary cleavages distributed along the region spanning residues 74-102. Accordingly, we identify three regions in pr[P.sup.Sc]: one N-terminal (residues 23-73) that is invariably PK-sensitive, one C-terminal (residues 103-231) that is invariably PK-resistant, and a third variable region (residues 74-102) where the site of the PK cleavage, likely reflecting the extent of the [Beta]-sheet structure, varies mostly as a function of the PrP genotype at codon 129.