Hyperhomocysteinemia and bleomycin hydrolase modulate the expression of mouse brain proteins involved in neurodegeneration.
Homocysteine (Hcy) is a risk factor for Alzheimer's disease (AD). Bleomycin hydrolase (BLMH) participates in Hcy metabolism and is also linked to AD. The inactivation of the Blmh gene in mice causes accumulation of Hcy-thiolactone in the brain and increases susceptibility to Hcy-thiolactone-induced seizures. To gain insight into brain-related Blmh function, we used two-dimensional IEF/SDS-PAGE gel electrophoresis and MALDI-TOF/TOF mass spectrometry to examine brain proteomes of Blmh-/- mice and their Blmh+/+ littermates fed with a hyperhomocysteinemic high-Met or a control diet. We found that: (1) proteins involved in brain-specific function (Ncald, Nrgn, Stmn1, Stmn2), antioxidant defenses (Aop1), cell cycle (RhoGDI1, Ran), and cytoskeleton assembly (Tbcb, CapZa2) were differentially expressed in brains of Blmh-null mice; (2) hyperhomocysteinemia amplified effects of the Blmh-/- genotype on brain protein expression; (3) proteins involved in brain-specific function (Pebp1), antioxidant defenses (Sod1, Prdx2, DJ-1), energy metabolism (Atp5d, Ak1, Pgam-B), and iron metabolism (Fth) showed differential expression in Blmh-null brains only in hyperhomocysteinemic animals; (4) most proteins regulated by the Blmh-/- genotype were also regulated by high-Met diet, albeit in the opposite direction; and (5) the differentially expressed proteins play important roles in neural development, learning, plasticity, and aging and are linked to neurodegenerative diseases, including AD. Taken together, our findings suggest that Blmh interacts with diverse cellular processes from energy metabolism and anti-oxidative defenses to cell cycle, cytoskeleton dynamics, and synaptic plasticity essential for normal brain homeostasis and that modulation of these interactions by hyperhomocysteinemia underlies the involvement of Hcy in AD.
Institute of Bioorganic Chemistry, Poznań, Poland.
Joanna
J
Suszyńska-Zajczyk
Institute of Bioorganic Chemistry, Poznań, Poland.
Magdalena
M
Luczak
Institute of Bioorganic Chemistry, Poznań, Poland.
Lukasz
L
Marczak
Institute of Bioorganic Chemistry, Poznań, Poland Department of Biochemistry and Biotechnology, University of Life Sciences, Poznań, Poland Department of Microbiology & Molecular Genetics, Rutgers-New Jersey Medical School, International Center for Public Health, Newark, NJ, USA.
Hieronim
H
Jakubowski
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D006710:Homocysteine / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D040901:Proteomics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D009419:Nerve Tissue Proteins; D006710:Homocysteine; D003546:Cysteine Endopeptidases; C031262:bleomycin hydrolase
Alzheimer's disease; Blmh-null mouse; bleomycin hydrolase; brain proteome; dietary hyperhomocysteinemia; homocysteine; neurodegenerative diseases