Parkin-deficient mice are not a robust model of parkinsonism - PubMed (original) (raw)

Parkin-deficient mice are not a robust model of parkinsonism

Francisco A Perez et al. Proc Natl Acad Sci U S A. 2005.

Abstract

Mutations in the human parkin gene cause autosomal recessive juvenile parkinsonism, a heritable form of Parkinson's disease (PD). To determine whether mutations in the mouse parkin gene (Park2) also result in a parkinsonian phenotype, we generated mice with a targeted deletion of parkin exon 2. Using an extensive behavioral screen, we evaluated neurological function, motor ability, emotionality, learning, and memory in aged Parkin-deficient mice. The behavioral profile of Parkin-deficient mice on a B6;129S4 genetic background was strikingly similar to that of control mice, and most differences were not reproducible by using coisogenic mice on a 129S4 genetic background. Moreover, catecholamine levels in the striatum, olfactory bulb, and spinal cord of Parkin-deficient mice were normal. In contrast to previous studies using independently generated Parkin-deficient mice, we found no evidence for nigrostriatal, cognitive, or noradrenergic dysfunction. Understanding why Parkin-deficient mice do not exhibit robust signs of parkinsonism could advance knowledge and treatment of PD.

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Figures

Fig. 1.

Fig. 1.

Behavioral profile of Parkin-deficient mice (B6;129S4) at various ages. An interactive version of this figure with links to detailed methods, results, and statistical analyses is available in Supporting Appendix 1. Differences between WT and KO mice at the 0.01 < _P_ < 0.05 level are indicated by a medium-gray box; differences between WT and KO mice at the _P_ < 0.01 level are indicated by a black box. After controlling the false discovery rate at 0.10, none of these findings would be considered statistically significant. Light-gray boxes reflect tests in which no differences were detected (_P_ > 0.05). Previously reported behavioral findings in Parkin-deficient mice that were not reproducible in the present study are indicated with an “X.” (A) KO mice weighed less on a B6;129S4 genetic background but not on a 129S4 genetic background. (B)KO mice demonstrated appropriate body-temperature regulation and nest-building behavior in response to cold exposure but consumed more food than WT mice. (C) KO mice exhibited a reduced visual placement response. (D) KO mice were less likely to display aggressive behavior. (E) KO mice displayed increased sensitivity in the acoustic-startle response; 129S4 mice did not display a startle response. (F) The reduction in daytime locomotor activity from Day 1 to Day 2 was more dramatic for KO mice. (G) Locomotor activity for KO mice was greater during the second dark cycle. (H) KO mice were more likely to grip onto the rotarod. (I and J) KO mice demonstrated increased endurance, but only for one trial; no differences were detected with 129S4 mice. (K) KO mice took longer to orient themselves; no differences were detected with 129S4 mice. (L and M) KO mice took less time to turn, but only for one trial. (N) KO mice spent more time immobile only during the third minute of the test. (O) KO mice displayed enhanced learning; 129S4 mice could not be tested because of long latencies to enter the dark chamber during training.

Fig. 2.

Fig. 2.

Intact neurological function, motor ability, emotionality, learning, and memory in 18- to 22-month-old Parkin-deficient mice. (A) Latency to remove labels in the adhesive-removal test for somatosensory function. (B) Exploratory locomotor activity over 4 h. (C) Latency to fall off the rotarod for four trials per day over 5 days. (D) Time spent immobile during the forced-swim test for depression-related behavior. (E) Latency to locate the platform in the Morris water maze test for learning and memory. (F) Locomotor activity for 2 h after a saline injection (Sal) or after repeated administration of amphetamine (A1 and A2) in 3-month-old mice. Normally distributed data are shown as mean and SEM or 95% confidence interval (CI); data that are not normally distributed are shown as median and quartiles (Q25, Q75). Full results are published in Supporting Appendix 1.

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