Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson's disease

Melanie Bousquet; Karl Gue; Vincent Emond; Pierre Julien; Jing X. Kang; Francesca Cicchetti; Frederic Calon

doi:10.1194/jlr.M011692

Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson's disease

^*Centre de Recherche du CHUL (CHUQ), Axe Neurosciences, Québec, QC, Canada
^†Faculté de Pharmacie, Université Laval, Québec, QC, Canada
^††Département de Psychiatrie & Neurosciences, Faculté de Médecine, Université Laval, Québec, QC, Canada
^§Centre de Recherche sur les Maladies Lipidiques, CHUL (CHUQ), Québec, QC, Canada, Massachusetts General Hospital and Medical School, Boston, MA
^**Department of Medicine, Massachusetts General Hospital and Medical School, Boston, MA

2To whom correspondence should be addressed. e-mail: Francesca.Cicchetti{at}crchul.ulaval.ca; Frederic.Calon{at}crchul.ulaval.ca

Abstract

We have recently identified a neuroprotective role for omega-3 polyunsaturated fatty acids (n-3 PUFAs) in a toxin-induced mouse model of Parkinson's disease (PD). Combined with epidemiological data, these observations suggest that low n-3 PUFA intake is a modifiable environmental risk factor for PD. In order to strengthen these preclinical findings as prerequisite to clinical trials, we further investigated the neuroprotective role of n-3 PUFAs in Fat-1 mice, a transgenic model expressing an n-3 fatty acid desaturase converting n-6 PUFAs into n-3 PUFAs. Here, we report that the expression of the fat-1 transgene increased cortical n-3:n-6 PUFA ratio (+28%), but to a lesser extent than dietary supplementation (92%). Such a limited endogenous production of n-3 PUFAs in the Fat-1 mouse was insufficient to confer neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity as assessed by dopamine levels, tyrosine hydroxylase (TH)-positive neurons and fibers, as well as nigral Nurr1 and dopamine transporter (DAT) mRNA expression. Nevertheless, higher cortical docosahexaenoic acid (DHA) concentrations were positively correlated with markers of nigral dopaminergic neurons such as the number of TH-positive cells, in addition to Nurr1 and DAT mRNA levels. These associations are consistent with the protective role of DHA in a mouse model of PD. Taken together, these data suggest that dietary intake of a preformed DHA supplement is more effective in reaching the brain and achieving neuroprotection in an animal model of PD.

Footnotes

↵1 F. Cicchetti and F. Calon are co-senior authors.
Abbreviations:

BDNF

brain-derived neurotrophic factor

COX

cyclooxygenase

DA

dopamine, DAergic, dopaminergic

DAT

dopamine transporter

DHA

docosahexaenoic acid

DOPAC

3,4-dihydroxyphenylacetic acid

EPA

eicosapentaenoic acid

GFAP

glial fibrillary acidic protein

HVA

homovanillic acid

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NonTg

nontransgenic

SNpc

substantia nigra pars compacta

TH

tyrosine hydroxylase
This study was supported by Parkinson Society Canada, and by the Institute of Nutrition, Metabolism and Diabetes (INMD) of the Canadian Institutes of Health Research (CIHR) and the Canada Foundation for Innovation (F. Cicchetti and F. Calon). M. Bousquet was supported by a Vanier Canada Graduate Scholarship from the CIHR. The work of F. Calon was supported by a New Investigator Award from the Clinical Research Initiative and the CIHR Institute of Aging (CAN-76833). The work of F. Cicchetti was supported by a New Investigator Award from the CIHR.