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The Journal of Neuroscience, September 27, 2006, 26(39):9975-9982; doi:10.1523/JNEUROSCI.2595-06.2006

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Neurobiology of Disease
Targeted Deletion of a Single Sca8 Ataxia Locus Allele in Mice Causes Abnormal Gait, Progressive Loss of Motor Coordination, and Purkinje Cell Dendritic Deficits

Yungui He,^1,2 Tao Zu,¹ Kellie A. Benzow,^1,2 Harry T. Orr,^1,2 H. Brent Clark,^1,2,3 and Michael D. Koob^1,2

¹Institute of Human Genetics, ²Laboratory of Medicine and Pathology, and ³Neurology, University of Minnesota, Minneapolis, Minnesota 55455

Correspondence should be addressed to Michael D. Koob, Institute of Human Genetics, MMC 206, University of Minneapolis Hospital and Clinic, 420 Delaware Street SE, University of Minnesota, Minneapolis, MN 55455. Email: koobx001{at}umn.edu

Spinocerebellar ataxia type 8 (SCA8) patients typically have a slowly progressive, adult-onset ataxia. SCA8 is dominantly inherited and is caused by large CTG repeat expansions in the untranslated antisense RNA of the Kelch-like 1 gene (KLHL1), but the molecular mechanism through which this expansion leads to disease is still unknown. To more fully characterize the underlying molecular mechanisms involved in SCA8, we developed a mouse model in which Klhl1 is deleted in either all tissues or is deleted specifically in Purkinje cells only. We found that mice that are either homozygous or heterozygous for the Klhl1 deletion have significant gait abnormalities at an early age and develop a significant loss of motor coordination by 24 weeks of age. This loss progresses more rapidly in homozygous knock-outs. Mice with Klhl1 specifically deleted in only Purkinje cells had a loss of motor coordination that was almost identical to the total-tissue deletion mice. Finally, we found significant Purkinje cell dendritic deficits, as measured by the thickness of the molecular layer, in all mice in which Klhl1 was deleted (both total and Purkinje cell-specific deletions) and an intermediate reduction in molecular layer thickness in mice with reduced levels of Klhl1 expression (heterozygous deletions). The results from this mouse model show that even a partial loss of Klhl1 function leads to degeneration of Purkinje cell function and indicates that loss of KLHL1 activity is likely to play a significant part in the underlying pathophysiology of SCA8.

Key words: ataxia; halpoinsufficiency; knock-out; neurodegeneration; Purkinje cell; SCA8

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Received June 20, 2006; revised Aug. 21, 2006; accepted Aug. 24, 2006.

Correspondence should be addressed to Michael D. Koob, Institute of Human Genetics, MMC 206, University of Minneapolis Hospital and Clinic, 420 Delaware Street SE, University of Minnesota, Minneapolis, MN 55455. Email: koobx001{at}umn.edu

This article has been cited by other articles:

				S. Jiang, S. Seng, H. K. Avraham, Y. Fu, and S. Avraham Process Elongation of Oligodendrocytes Is Promoted by the Kelch-related Protein MRP2/KLHL1 J. Biol. Chem., April 20, 2007; 282(16): 12319 - 12329. [Abstract] [Full Text] [PDF]

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