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

• Main Authors: Chakrabarti Lisa, Eng Jeremiah, Ivanov Nishi, Garden Gwenn A, La Spada Albert R
• Format: Article
• Language: English
• Published: BMC 2009-07-01
• Series: Molecular Brain
• Online Access: http://www.molecularbrain.com/content/2/1/24

<p>Abstract</p> <p>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 (<it>pcd</it>) 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 <it>pcd </it>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 <it>pcd </it>mice. BAX null status did not suppress Purkinje neuron death in <it>pcd </it>mice, indicating that classic apoptosis is not responsible for Purkinje cell loss. Interestingly, LC3 Western blot analysis and GFP-LC3 immunostaining of degenerating <it>pcd </it>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 <it>pcd </it>cerebellum, our findings suggest that <it>pcd </it>Purkinje cell neurons can execute effective autophagy. However, our results support a role for dysregulated autophagy activation in <it>pcd</it>, and suggest that increased or aberrant mitophagy contributes to the Purkinje cell degeneration in <it>pcd </it>mice.</p>