Dendritic Excitability and Protein Kinase C Activity Regulate Purkinje Neuron Dendrite Degeneration in Cerebellar Ataxia
Chopra, Ravi
2020
Abstract
Spinocerebellar ataxias (SCAs) are hereditary neurodegenerative disorders that are united by their autosomal dominant inheritance and their common clinical feature: cerebellar ataxia. Cerebellar ataxia is a disorder of impaired motor coordination, and in many SCAs the cause of degraded motor coordination is understood to be degeneration of cerebellar Purkinje neurons. The degeneration of Purkinje neurons in many SCAs is thought to progress from degeneration of the elaborate Purkinje neuron dendrite arbor to eventual cell death. Although it is likely that the early dendrite degeneration contributes substantially to motor impairment, the cellular processes which drive dendrite degeneration remain very poorly understood. It is known that synaptic inputs and intrinsic excitability shape Purkinje neuron dendrites during development, and several studies in different SCA models have suggested that altered synaptic input or action potential firing contributes to Purkinje neuron degeneration. Not yet explored in any of the SCA models is whether the physiology of the Purkinje neuron dendritic shaft are altered. In a mouse model of spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that SCA1 Purkinje neurons would show an increase in intrinsic dendritic excitability that promotes dendrite degeneration. Our studies identified an increase in intrinsic dendritic excitability throughout the course of dendritic degeneration, and we showed that this increased dendritic excitability was associated with changes in expression of several channels that regulate dendritic excitability. Subsequently, we demonstrated that normalizing dendritic excitability exerts a dendro-protective effect in SCA1 Purkinje neurons, supporting the hypothesis that increased intrinsic dendritic excitability drives SCA1 Purkinje neuron dendrite degeneration. In our attempts to uncover the pathway(s) by which increased dendritic excitability drives SCA1 Purkinje neuron dendrite degeneration, we uncovered a large increase in phosphorylation of protein kinase C (PKC) enzyme targets in SCA1 mice and SCA1 patient tissue. PKC activity is an important regulator of Purkinje neuron dendritic structure, and we hypothesized that increased PKC activity downstream of increased excitability promotes dendritic degeneration. Surprisingly, suppression of PKC activity in SCA1 mice resulted in accelerated dendritic degeneration, suggesting that the increased PKC activation is dendro-protective. A similar dendro-protective effect was observed in a model of a different cerebellar ataxia, Spinocerebellar ataxia type 2 (SCA2). Studies from the SCA1 mice suggest that PKC enzymes may be exerting their dendro-protective effect by counteracting (although incompletely) increases in dendritic excitability, further supporting the role that dendritic excitability plays as a driver of Purkinje neuron dendritic degeneration. This thesis establishes both intrinsic dendritic excitability and PKC activity as important regulators of Purkinje neuron dendrite degeneration in SCA1 and beyond. The results provide clinically-relevant therapeutic targets, and also provide a novel conceptual framework for understanding Purkinje neuron dendrite remodeling in health and disease. Together, these findings establish that Purkinje neuron dendrite degeneration is in fact a regulated process, with dendrite excitability and PKC activity specifically identified as two key regulators of that process.Subjects
Neuroscience Neurodegeneration Cerebellar Ataxia Dendrites Ion channels Protein kinase C
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