alpha-synuclein and ursodoxicoltaurine

Calcium homeostasis plays a crucial role in neuronal development and disease. Calbindin-D. We used CaBP-9k knockout (KO) mice to investigate the roles of these gene in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. We used anatomical and biochemical approaches to characterize functional abnormalities of the brain in the CaBP-9k KO mice.. We found that the brains of CaBP-9k KO mice have increased APP/β-amyloid, Tau, and α-synuclein accumulation and endoplasmic reticulum (ER) stress-induced apoptosis. Neurons deficient for these CaBP-9k had abnormal intracellular calcium levels and responses. ER stress inhibitor TUDCA reduced ER stress-induced apoptosis and restored ER stress- and apoptosis-related proteins expression to wild-type levels in CaBP-9k KO mice. Furthermore, treatment with TUDCA rescued the abnormal memory and motor behaviors exhibited by older CaBP-9k KO mice.. Our results suggest that a loss of CaBP-9k may contribute to the onset and progression of neurodegenerative diseases.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Brain; Calbindins; Calcium; Cell Proliferation; Cells, Cultured; Endoplasmic Reticulum Stress; Maze Learning; Memory Disorders; Mice; Mice, Knockout; Motor Activity; Neurons; Parkinson Disease; Risk Factors; RNA, Small Interfering; tau Proteins; Taurochenodeoxycholic Acid

Topics: alpha-Synuclein; Animals; Brain; Cell Death; Cell Line; Glutathione Peroxidase; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning; NF-E2-Related Factor 2; Oxidative Stress; Parkinson Disease, Secondary; Reactive Oxygen Species; RNA, Small Interfering; Taurochenodeoxycholic Acid

How genetic and environmental factors interact in Parkinson disease is poorly understood. We have now compared the patterns of vulnerability and rescue of Caenorhabditis elegans with genetic modifications of three different genetic factors implicated in Parkinson disease (PD). We observed that expressing alpha-synuclein, deleting parkin (K08E3.7), or knocking down DJ-1 (B0432.2) or parkin produces similar patterns of pharmacological vulnerability and rescue. C. elegans lines with these genetic changes were more vulnerable than nontransgenic nematodes to mitochondrial complex I inhibitors, including rotenone, fenperoximate, pyridaben, or stigmatellin. In contrast, the genetic manipulations did not increase sensitivity to paraquat, sodium azide, divalent metal ions (Fe(II) or Cu(II)), or etoposide compared with the nontransgenic nematodes. Each of the PD-related lines was also partially rescued by the antioxidant probucol, the mitochondrial complex II activator, D-beta-hydroxybutyrate, or the anti-apoptotic bile acid tauroursodeoxycholic acid. Complete protection in all lines was achieved by combining d-beta-hydroxybutyrate with tauroursodeoxycholic acid but not with probucol. These results show that diverse PD-related genetic modifications disrupt the mitochondrial function in C. elegans, and they raise the possibility that mitochondrial disruption is a pathway shared in common by many types of familial PD.

Topics: 3-Hydroxybutyric Acid; alpha-Synuclein; Amino Acid Sequence; Animals; Animals, Genetically Modified; Antioxidants; Apoptosis; Benzoates; Benzothiazoles; Bile Acids and Salts; Caenorhabditis elegans; Cholagogues and Choleretics; Copper; Disease Models, Animal; Electron Transport Complex I; Gene Deletion; Gene Expression Regulation; Gene Library; Genetic Techniques; Humans; Immunoblotting; Intracellular Signaling Peptides and Proteins; Ions; Iron; Mitochondria; Molecular Sequence Data; Mutagenesis; Mutation; Neurons; Oncogene Proteins; Oxygen Consumption; Paraquat; Parkinson Disease; Polyenes; Probucol; Protein Deglycase DJ-1; Pyrazoles; Pyridazines; RNA, Small Interfering; Rotenone; Sequence Homology, Amino Acid; Sodium Azide; Taurochenodeoxycholic Acid; Thiazoles; Time Factors; Transgenes; Ubiquitin-Protein Ligases