Autophagy activation and enhanced mitophagy characterize the Purkinje cells of pcd mice prior to neuronal death

被引:90
作者
Chakrabarti, Lisa [1 ]
Eng, Jeremiah [1 ]
Ivanov, Nishi [2 ]
Garden, Gwenn A. [2 ,4 ]
La Spada, Albert R. [1 ,2 ,3 ,4 ,5 ,6 ]
机构
[1] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA
[2] Univ Washington, Dept Neurol, Seattle, WA 98195 USA
[3] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA
[4] Univ Washington, Ctr Neurogenet & Neurotherapeut, Seattle, WA 98195 USA
[5] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA
[6] Univ Calif San Diego, Dept Cellular & Mol Med, San Diego, CA 92103 USA
来源
MOLECULAR BRAIN | 2009年 / 2卷
关键词
Purkinje Cell; Purkinje Neuron; Autophagy Pathway; Autophagy Activation; Homozygous Mouse;
D O I
10.1186/1756-6606-2-24
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Purkinje cells are a class of specialized neurons in the cerebellum, and are among the most metabolically active of all neurons, as they receive immense synaptic stimulation, and provide the only efferent output from the cerebellum. Degeneration of Purkinje cells is a common feature of inherited ataxias in humans and mice. To understand Purkinje neuron degeneration, investigators have turned to naturally occurring Purkinje cell degeneration phenotypes in mice to identify key regulatory proteins and cellular pathways. The Purkinje cell degeneration (pcd) mouse is a recessive mutant characterized by complete and dramatic post-natal, cell autonomous Purkinje neuron degeneration and death. As the basis of Purkinje cell death in pcd is unresolved, and contradictory data has emerged for the role of autophagy in Purkinje cell degeneration, we studied the mechanism of Purkinje cell death in pcd mice. BAX null status did not suppress Purkinje neuron death in pcd mice, indicating that classic apoptosis is not responsible for Purkinje cell loss. Interestingly, LC3 Western blot analysis and GFP-LC3 immunostaining of degenerating pcd cerebellum revealed activation of the autophagy pathway. Ultrastructural studies confirmed increased autophagy pathway activity in Purkinje cells, and yielded evidence for mitophagy, in agreement with LC3 immunoblotting of cerebellar fractions. As p62 levels were decreased in pcd cerebellum, our findings suggest that pcd Purkinje cell neurons can execute effective autophagy. However, our results support a role for dysregulated autophagy activation in pcd, and suggest that increased or aberrant mitophagy contributes to the Purkinje cell degeneration in pcd mice.
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页数:9
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