Impact of DHA intake in a mouse model of synucleinopathy.

Polyunsaturated fatty acids omega-3 (n-3 PUFA), such as docosahexaenoic acid (DHA), have been shown to prevent, and partially reverse, neurotoxin-induced nigrostriatal denervation in animal models of Parkinson's disease (PD). However, the accumulation of α-synuclein (αSyn) in cerebral tissues is equally important to the pathophysiology. To determine whether DHA intake improves various aspects related to synucleinopathy, ninety male mice overexpressing human αSyn under the Thy-1 promoter (Thy1-αSyn) were fed one of three diets (specially formulated control, low n-3 PUFA or high DHA) and compared to non-transgenic C57/BL6 littermate mice exposed to a control diet. Thy1-αSyn mice displayed impaired motor skills, lower dopaminergic neuronal counts within the substantia nigra (-13%) in parallel to decreased levels of the striatal dopamine transporter (DAT) (-24%), as well as reduced NeuN (-41%) and synaptic proteins PSD-95 (-51%), synaptophysin (-80%) and vesicular acetylcholine transporter (VChAT) (-40%) in the cerebral cortex compared to C57/BL6 mice. However, no significant difference in dopamine concentrations was observed by HPLC analysis between Thy1-αSyn and non-transgenic C57/BL6 littermates under the control diet. The most striking finding was a favorable effect of DHA on the survival/longevity of Thy1-αSyn mice (+51% survival rate at 12months of age). However, dietary DHA supplementation did not have a significant effect on other parameters examined in this study, despite increased striatal dopamine concentrations. While human αSyn monomers and oligomers were detected in the cortex of Thy1-αSyn mice, the effects of the diets were limited to a small increase of 42kDa oligomers in insoluble protein fractions upon n-3 PUFA deprivation. Overall, our data indicate that a diet rich in n-3 PUFA has a beneficial effect on the longevity of a murine model of α-synucleinopathy without a major impact on the dopamine system and motor impairments, nor αSyn levels.

Additive neurorestorative effects of exercise and docosahexaenoic acid intake in a mouse model of Parkinson's disease.

JOURNAL/nrgr/04.03/01300535-202502000-00033/figure1/v/2024-05-28T214302Z/r/image-tiff There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson's disease after diagnosis. Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids, such as docosahexaenoic acid, and exercise in Parkinson's disease, we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway. First, mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation. Four weeks after lesion, animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks. During this period, the animals had access to a running wheel, which they could use or not. Docosahexaenoic acid treatment, voluntary exercise, or the combination of both had no effect on (i) distance traveled in the open field test, (ii) the percentage of contraversive rotations in the apomorphine-induction test or (iii) the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta. However, the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum. Compared to docosahexaenoic acid treatment or exercise alone, the combination of docosahexaenoic acid and exercise (i) improved forelimb balance in the stepping test, (ii) decreased the striatal DOPAC/dopamine ratio and (iii) led to increased dopamine transporter levels in the lesioned striatum. The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson's disease.