Protein kinase C to the Rescue in Spinocerebellar Ataxias

Written By Dr. Marija Cvetanovic   Edited by Dr. Sriram Jayabal

Protein kinase C: one protein that may help to protect against cerebellar neuronal dysfunction & death in spinocerebellar ataxias

Among the estimated 86 billion brain cells (known as “neurons”) in the human body (Azevedo et al., 2009), there is a small population of cells called Purkinje neurons. Though they only constitute a modest ~14-16 million cells, (Nairn et al., 1989), death or dysfunction in Purkinje neurons can cause you to lose your ability to walk coherently – a clinical symptom known as “ataxia.” This is because Purkinje neurons are the major work horse of the cerebellum, which is the part of the brain that fine-tunes our movement. While different types of hereditary spinocerebellar ataxias (SCAs) are caused by mutations in different genes, they all exhibit one thing in common: Purkinje neurons undergo severe degeneration. Neither the reasons for this selective vulnerability of Purkinje neurons in ataxia, nor how to increase their resistance to degeneration, are clear.

Three cartoon brains
Image courtesy of the The Internet Archive/Nielsen Malaysia

Recent work from Chopra and colleagues in the laboratory of Dr. Vikram Shakkottai may offer an explanation for this mystery. They show that the activity of a protein called “protein kinase C” has a protective influence on the function and survival of Purkinje neurons in two different types of cerebellar ataxias (SCA1 and SCA2). Protein kinase C belongs to the very important group of proteins called kinases. Kinases modulate the function of many other proteins that play a critical role in regulating neuronal function and survival. They do this by adding negatively-charged phosphate groups to the proteins that can, for example, alter their structure, and/or ability to interact with other proteins. While protein kinase C is expressed in many different types of neurons across the brain, it is particularly important for the proper functioning of Purkinje neurons. There is more protein kinase C produced in Purkinje neurons than in any other neurons in the brain, and loss of protein kinase C causes dysfunction of Purkinje neurons and ataxia in mice (Hirai, 2018). Moreover, mutations that occur directly in protein kinase C causes SCA type 14, further reiterating the important role played by protein kinase C in the cerebellum (Yabe et al., 2003, van de Warrenburg et al, 2003, Chen et al., 2003).

Given the importance of protein kinase C for Purkinje neurons, the authors decided to examine whether it plays a role in SCAs where protein kinase C is not directly mutated. For this study, the authors used mouse models of two different dominantly-inherited SCAs: SCA1 and SCA2. These mice develop the symptoms of SCAs, such as a loss of balance during movement, and also exhibit pathological changes in Purkinje neurons that are reminiscent of what is seen in SCA patients as the disease progresses. Furthermore, using these animal models allows us to study the disease progression in a much shorter time frame (in months), compared to how it progresses in humans (in years), as well as to pre-clinically test the role of different factors in disease symptoms.

Using these animal models, the authors found that the activity of protein kinase C is increased in Purkinje neurons in SCA1 and SCA2 mouse models. More importantly, studying cerebellar tissue from patients confirmed that protein kinase C activity is enhanced in human SCA1. What does an increase in protein kinase C activity mean to these neurons? To investigate this, the authors used genetic tools to inhibit PKC in the SCA1 and SCA2 mice. They found that inhibiting protein kinase C worsens the pathology and impairs the function of Purkinje neurons in these mice. Thus, the authors concluded that increased protein kinase C activity, which was observed in SCA1 and SCA2 mice and in SCA1 patients, acts to protect Purkinje neurons in these SCAs. However, it is important to note that no tests of balance during movement were performed in this study – therefore, it remains to be shown whether increasing the protein kinase C’s protective effect on Purkinje neurons translates into diminished symptoms of ataxia.

While this work focused on mouse models of SCA1 and SCA2, the authors suggest that these findings could be extended to many other cerebellar ataxias because of the pivotal role played by protein kinase C in Purkinje neurons. For example, these results could increase our understanding of why Purkinje neurons are dysfunctional in SCA14, a form of SCA caused by a mutation in protein kinase C. Moreover, these findings suggest that protein kinase C may act as a common modifier of Purkinje neuron dysfunction in ataxia. This is further supported by genetic evidence that the mutant proteins that cause several other types of ataxia, including SCA13, SCA15/16, and SCA41 (Adachi et al., 2008, Desai et al., 2008, Matter et al., 1998), are known to be modulated by protein kinase C.

Finally, this study paves the way to a potential new therapy, where pharmacological activation of protein kinase C may therapeutically protect Purkinje neurons in SCA patients. Pre-clinical studies in animal models are needed to evaluate the efficacy of such a therapy. Overall, this is a study is of great significance, as protein kinase C might be a common denominator in a multitude of SCAs – and, likewise, could be targeted to devise a “one for all” therapy.

Key Terms

Purkinje neurons (PNs):  A type of neuron located in the cerebellum, where they help regulate fine movement. They are some of the largest neurons in the brain. Purkinje cell loss/pathology is a common feature in cerebellar ataxia.

Spinocerebellar ataxia type 1 (SCA1): A dominantly-inherited and fatal neurodegenerative disease caused by the abnormal expansion of CAG repeats in the gene ATXN1.

Protein kinase C (PKC): A protein that regulates the function and survival of cells by phosphorylating proteins in the cells.

Conflict of Interest Statement

The author and editor declare no conflicts of interests.

Citation of Article Reviewed

Ravi Chopra, Aaron H Wasserman, Stefan M Pulst, Chris I De Zeeuw, Vikram G Shakkottai; Protein kinase C activity is a protective modifier of Purkinje neuron degeneration in cerebellar ataxia, Human Molecular Genetics, Volume 27, Issue 8, 15 April 2018, Pages 1396–1410, https://doi.org/10.1093/hmg/ddy050