Loss of poly(ADP-ribose) glycohydrolase causes progressive neurodegeneration in Drosophila melanogaster.
Poly(ADP-ribosyl)ation has been suggested to be involved in regulation of DNA repair, transcription, centrosome duplication, and chromosome stability. However, the regulation of degradation of poly(ADP-ribose) and its significance are not well understood. Here we report a loss-of-function mutant Drosophila with regard to poly(ADP-ribose) glycohydrolase, a major hydrolyzing enzyme of poly(ADP-ribose). The mutant lacks the conserved catalytic domain of poly(ADP-ribose) glycohydrolase, and exhibits lethality in the larval stages at the normal development temperature of 25 degrees C. However, one-fourth of the mutants progress to the adult stage at 29 degrees C but showed progressive neurodegeneration with reduced locomotor activity and a short lifespan. In association with this, extensive accumulation of poly(ADP-ribose) could be detected in the central nervous system. These results suggest that poly(ADP-ribose) metabolism is required for maintenance of the normal function of neuronal cells. The phenotypes observed in the parg mutant might be useful to understand neurodegenerative conditions such as the Alzheimer's and Parkinson's diseases that are caused by abnormal accumulation of substances in nervous tissue.
Hanai
Shuji
S
Department of Biochemistry and Molecular Oncology, Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan.
Kanai
Masayuki
M
Ohashi
Sayaka
S
Okamoto
Keiji
K
Yamada
Mitsunori
M
Takahashi
Hitoshi
H
Miwa
Masanao
M
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000648:ultrastructure; D004247:DNA / Q000235:genetics; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D005260:Female; D017344:Genes, Insect; D006026:Glycoside Hydrolases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D009154:Mutation; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D013696:Temperature
D004247:DNA; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase