COMPARISON OF MOTOR PERFORMANCE, BRAIN BIOCHEMISTRY AND HISTOLOGY OF TWO A30P α-SYNUCLEIN TRANSGENIC MOUSE STRAINS

Three point mutations in the SNCA gene encoding alpha-synuclein (aSyn) have been associated with autosomal dominant forms of Parkinson's disease. To better understand the role of the A30P mutant aSyn, we compared two transgenic mouse strains: a knock-in mouse with an introduced A30P point mutation in the wild-type (WT) gene (Snca(tm(A30P))) and a transgenic (Tg) mouse overexpressing the human A30P aSyn gene under the orlon promoter [tg(Prnp-SNCA*A30P)]. The brain aSyn load, motor performance, brain dopamine (DA) and sensitivity to 6-hydroxydopamine (6-ODA) were studied in these mice. aSyn was evidently accumulating with age in all mice, particularly in tg(Prnp-SNCA*A30P) Tg mice. There were no robust changes in basal locomotor activities of the mice of either line at 6 months, but after 1 year, tg(Prnp-SNCA*A30P) Tg mice developed severe problems with vertical movements. However, the younger Tg mice had a reduced locomotor response to 1 mg/kg of D-amphetamine. Snca(tm(A30P)) mice with the targeted mutation (Tm) were slightly hyperactive at all ages. Less 6-OHDA was required in tg(Prnp-SNCA*A30P) Tg (1 mu g) than in WT (3 mu g) mice for an ipsilateral rotational bias by D-amphetamine. That was not seen with the Snca(tm(A30P)) strain. A small dose of 6-OHDA (0.33 mu g) led to contralateral rotations and elevated striatal DA in Tg/Tm mice of both lines but otherwise 6-ODA-induced striatal DA depletion was similar in all mice, indicating no A30P-aSyn-related toxin sensitivity. 3,4-Dihydroxyphenylacetic acid/DA-ratio was elevated in tg(Prnp-SNCA*A30P) mice, suggesting an enhanced DA turnover. This ratio and homovanillic acid/DA-ratio were declined in Snca(tm(A30P)) mice. Our results demonstrate that the two differently constructed A30P-aSyn mouse strains have distinct behavioral and biochemical characteristics, some of which are opposite. Since the two lines with the same background were not identically produced, the deviations found may be partially caused by factors other than aSyn-related genetic differences. (c) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.