Paraoxonase 1 (PON1) organophosphate hydrolysis is not reduced in ALS.
OBJECTIVE
Four recent studies report a genetic association of the paraoxonase locus with sporadic amyotrophic lateral sclerosis (ALS). We tested the hypothesis that this association correlates with functional changes in paraoxonase 1 (PON1, MIM 168820).


METHODS
Sera from 140 ALS participants; 153 age-, race-, and sex-matched controls; and 30 matched CSF samples were tested for paraoxonase, diazoxonase, and arylesterase activities. Participants with ALS were genotyped using tagging single nucleotide polymorphisms across the PON locus. Survival data and enzyme activity were correlated with genotype.


RESULTS
There was a trend toward increased paraoxonase activity in ALS compared with controls (mean control paraoxonase 701.9 +/- 469.7 U/L, mean ALS 792.5 +/- 574.1 U/L; p = 0.066 after correction) which correlated with increased frequency of the homozygous arginine (RR) variant of PON1(Q192R) (p = 0.004). There was no significant difference in PON1 protein levels, or arylesterase or diazoxonase activities. Organophosphate hydrolysis rates had no effect on ALS survival.


CONCLUSIONS
Contrary to expectations, PON1 protein, paraoxonase, diazoxonase, and arylesterase activities were not reduced in amyotrophic lateral sclerosis (ALS). The increase in PON1(R192) frequency in ALS in our study supports previous genetic susceptibility studies. Our findings suggest that the influence of PON1 polymorphisms on ALS susceptibility is not due to reduced organophosphate hydrolysis.
Wills
A-M
AM
Day Neuromuscular Research Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. awills@partners.org
Landers
J E
JE
Zhang
H
H
Richter
R J
RJ
Caraganis
A J
AJ
Cudkowicz
M E
ME
Furlong
C E
CE
Brown
R H
RH
D000690:Amyotrophic Lateral Sclerosis / Q000097:blood* / Q000201:enzymology* / Q000235:genetics; D043303:Aryldialkylphosphatase / Q000032:analysis / Q000097:blood* / Q000235:genetics; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D002265:Carboxylic Ester Hydrolases / Q000032:analysis / Q000097:blood / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D006868:Hydrolysis; D007527:Isoenzymes / Q000097:blood / Q000235:genetics; D008297:Male; D010755:Organophosphates / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011237:Predictive Value of Tests; D015854:Up-Regulation / Q000235:genetics
D015415:Biomarkers; D007527:Isoenzymes; D010755:Organophosphates; D002265:Carboxylic Ester Hydrolases; C019734:arylesterase; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human