Effects of the administration of Elovl5-dependent fatty acids on a spino-cerebellar ataxia 38 mouse model

Abstract

Background: Spinocerebellar ataxia 38 (SCA38) is a rare autosomal neurological disorder characterized by ataxia and cerebellar atrophy. SCA38 is caused by mutations of ELOVL5 gene. ELOVL5 gene encodes a protein, which elongates long chain polyunsaturated fatty acids (PUFAs). Knockout mice lacking Elovl5 recapitulate SCA38 symptoms, including motor coordination impairment and disruption of cerebellar architecture. We asked whether, in Elovl5 knockout mice (Elovl5^-/-), a diet with both ω3 and ω6 PUFAs downstream Elovl5 can prevent the development of SCA38 symptoms, and at which age such treatment is more effective. Elovl5^-/- mice were fed either with a diet without or containing PUFAs downstream the Elovl5 enzyme, starting at different ages. Motor behavior was assessed by the balance beam test and cerebellar structure by morphometric analysis.

Results: The administration from birth of the diet containing PUFAs downstream Elovl5 led to a significant amelioration of the motor performance in the beam test of Elovl5^-/- mice, with a reduction of foot slip errors at 6 months from 2.2 ± 0.3 to 1.3 ± 0.2 and at 8 months from 3.1 ± 0.5 to 1.9 ± 0.3. On the contrary, administration at 1 month of age or later had no effect on the motor impairment. The cerebellar Purkinje cell layer and the white matter area of Elovl5^{-/ -}mice were not rescued even by the administration of diet from birth, suggesting that the improvement of motor performance in the beam test was due to a functional recovery of the cerebellar circuitry.

Conclusions: These results suggest that the dietary intervention in SCA38, whenever possible, should be started from birth or as early as possible.

Keywords: Elovl5; Motor deficits; Polyunsaturated fatty acids; SCA38; Spino-cerebellar ataxia.

Fig. 1

Progression of motor impairment in Elovl5^−/− mice administered with a PUFA precursors diet. Bar graphs showing the number of errors at different ages (from 1 to 10th month of age) for wild type and Elovl5^−/− mice. Elovl5^−/− mice undergo a great worsening of motor coordination across months, while wild type mice, after the first month of age, show an almost unchanged mean number of errors with age (****P < 0.0001, Two-way ANOVA; n = 23 wild type mice, n = 18 Elovl5^−/− mice). Values are mean ± S.E.M

Fig. 2

Administration of a complete PUFA diet since birth on Elovl5 ^−/− mice slows down motor impairment. A Scheme of diet administration: one group composed of Elovl5^−/− (n = 18) and wild type mice (n = 17) received a diet providing them with both Elovl5 substrates and downstream products from birth (complete PUFA diet), while the other group of Elovl5^−/− (n = 38) and wild type mice (n = 38) received only PUFA precursors from birth (PUFA precursors only). B, C Bar graphs showing errors committed traversing the experimental apparatus at 1 month of age for wild type and Elovl5^−/−mice who received the two different diets (for wild type mice: *P < 0.05; for Elovl5^−/−mice P > 0.05, Unpaired Student’s t-test). D, E Motor performances at 6 months of age for Elovl5^−/−mice and wild type littermates receiving the two different diets from birth (for wild type mice: **P < 0.01; for Elovl5^−/−mice *P < 0.05, Unpaired Student’s t-test). F, G Motor performances at 8 months of age for Elovl5^−/− mice and control littermates compared to genotype matched PUFA precursors mice (P < 0.05, Unpaired Student’s t-test). Values are mean ± S.E.M

Fig. 3

Administration of a complete PUFA diet from 1 month of age in Elovl5^−/− and wild type mice. A Scheme of diet administration: one group composed of Elovl5^−/− (n = 20) and wild type mice (n = 19) received a diet providing them with both Elovl5 substrates and downstream products from 1 month of age (complete PUFA diet), while the other group of Elovl5^−/− (n = 18) and wild type mice (n = 20) received PUFA precursors only from birth (PUFA precursors only). B, C Bar graphs showing errors committed at 6 months of age when traversing the experimental apparatus for wild type and Elovl5^−/−mice who received the complete diet since 1 month of age compared to the group receiving the precursor diet only (for wild type mice: **P < 0.01, Unpaired Student’s t-test; for Elovl5^−/−mice P > 0.05, Unpaired Student’s t-test). D, E Bar graphs showing errors committed at 8 months of age when traversing the experimental apparatus by wild type and Elovl5^−/− mice receiving the two different diets (for wild type mice: **P < 0.01, Unpaired Student’s t-test; for Elovl5^−/−mice P = 0.07, Unpaired Student’s t-test). Values are mean ± S.E.M

Fig. 4

Administration of a complete PUFA diet on Elovl5^−/− mice in late adulthood does not ameliorate motor deficits. A Schematic representation of the experimental design. One group composed of 10 months old Elovl5^−/− (n = 8) and wild type mice (n = 16) received the complete PUFA diet since 10 months of age and the motor performance was checked after two months of administration. B, C Mean number of errors committed traversing the experimental apparatus for both wild type and Elovl5^−/− mice at 10 (white bars) and 12 months (grey bars). As shown, the complete diet administered in late adulthood fails to rescue motor coordination impairment of Elovl5^−/− mice (for both wild type and Elovl5^−/− mice: P > 0.05, Unpaired Student’s t-test). Values are mean ± S.E.M