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PMID:16952463

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Citation

Wang, T, Parris, J, Li, L and Morgan, JI (2006) The carboxypeptidase-like substrate-binding site in Nna1 is essential for the rescue of the Purkinje cell degeneration (pcd) phenotype. Mol. Cell. Neurosci. 33:200-13

Abstract

The Purkinje cell degeneration (pcd) phenotype is characterized by adult onset neurodegeneration resulting from mutations in Nna1, a gene encoding an intracellular protein with a putative metallocarboxypeptidase domain. As Nna1 is also induced in axotomized motor neurons, the elucidation of its function can shed light on previously unsuspected mechanisms common to degenerative and regenerative responses. Structural modeling revealed that Nna1 and three related gene products constitute a new subfamily of metallocarboxypeptidases with a distinctive substrate-binding site. To test whether the metallocarboxypeptidase domain is functionally essential, transgenic mice were generated that expressed Nna1 or a substrate-binding site mutant of Nna1 selectively in Purkinje cells using the L7/pcp2 promoter. When bred onto a homozygous pcd(3J) background, wild type but not mutant Nna1 rescued ataxic behavior and Purkinje cell loss. Therefore, loss of Nna1 in Purkinje cells leads directly to their degeneration and Nna1's carboxypeptidase domain is essential for survival of these neurons.

Links

PubMed Online version:10.1016/j.mcn.2006.07.009

Keywords

Amino Acid Sequence; Animals; Ataxia/pathology; Ataxia/physiopathology; Binding Sites; Carboxypeptidases/chemistry; Carboxypeptidases/genetics; Carboxypeptidases/metabolism; Catalytic Domain; Female; GTP-Binding Proteins/chemistry; GTP-Binding Proteins/genetics; GTP-Binding Proteins/metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Molecular Sequence Data; Mutagenesis; Nerve Degeneration/pathology; Nerve Degeneration/physiopathology; Phenotype; Promoter Regions, Genetic/genetics; Protein Structure, Tertiary; Purkinje Cells/pathology; Purkinje Cells/physiology; Serine-Type D-Ala-D-Ala Carboxypeptidase/chemistry; Serine-Type D-Ala-D-Ala Carboxypeptidase/genetics; Serine-Type D-Ala-D-Ala Carboxypeptidase/metabolism; Zinc/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:CBPC1

acts_upstream_of_or_within

GO:0007628: adult walking behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857523

P

Seeded From UniProt

complete


See also

References

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