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.