title: CCP1/Nna1 functions in protein turnover in mouse brain: Implications for cell death in Purkinje cell degeneration mice.
abstract: Purkinje cell degeneration (pcd) mice have a mutation within the gene encoding cytosolic carboxypeptidase 1 (CCP1/Nna1), which has homology to metallocarboxypeptidases. To assess the function of CCP1/Nna1, quantitative proteomics and peptidomics approaches were used to compare proteins and peptides in mutant and wild-type mice. Hundreds of peptides derived from cytosolic and mitochondrial proteins are greatly elevated in pcd mouse hypothalamus, amygdala, cortex, prefrontal cortex, and striatum. However, the major proteins detected on 2-D gel electrophoresis were present in mutant and wild-type mouse cortex and hypothalamus at comparable levels, and proteasome activity is normal in these brain regions of pcd mice, suggesting that the increase in cellular peptide levels in the pcd mice is due to reduced degradation of the peptides downstream of the proteasome. Both nondegenerating and degenerating regions of pcd mouse brain, but not wild-type mouse brain, show elevated autophagy, which can be triggered by a decrease in amino acid levels. Taken together with previous studies on CCP1/Nna1, these data suggest that CCP1/Nna1 plays a role in protein turnover by cleaving proteasome-generated peptides into amino acids and that decreased peptide turnover in the pcd mice leads to cell death.
authors.affiliation: Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Iryna
authors.initials: I
authors.lastname: Berezniuk
authors.forename: Juan
authors.initials: J
authors.lastname: Sironi
authors.forename: Myrasol B
authors.initials: MB
authors.lastname: Callaway
authors.forename: Leandro M
authors.initials: LM
authors.lastname: Castro
authors.forename: Izaura Y
authors.initials: IY
authors.lastname: Hirata
authors.forename: Emer S
authors.initials: ES
authors.lastname: Ferro
authors.forename: Lloyd D
authors.initials: LD
authors.lastname: Fricker
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D016923:Cell Death; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D040901:Proteomics; D011689:Purkinje Cells / Q000473:pathology*; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase / Q000502:physiology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000596:Amino Acids; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase; C420042:Agtpbp1 protein, mouse; D019204:GTP-Binding Proteins