Material below summarizes the article Spinocerebellar Ataxia Type 6 Protein Aggregates Cause Deficits in Motor Learning and Cerebellar Plasticity, published on June 10, 2015, in JNeurosci and authored by Melanie D. Mark, Martin Krause, Henk-Jan Boele, Wolfgang Kruse, Stefan Pollok, Thomas Kuner, Deniz Dalkara, Sebastiaan Koekkboek, Chris I. De Zeeuw, and Stefan Herlitze.
In humans, several mutations in a particular calcium channel, the P/Q type, lead to neurological diseases, one of which manifests to ataxia. Ataxia is a disorder where an individual loses coordination or control of muscle movement. SCA6, or spinocerebellar ataxia type 6, is a movement disorder, which results in the loss of a special type of neuron in the cerebellum called Purkinje cells. These neurons process sensory information to coordinate movements. The disease has a late onset and develops in the second period of life. Patients are often wheelchair-bound, and no therapies are available.
SCA6 belongs together with Chorea Huntington, a family of polyglutamine (polyQ) diseases. These diseases contain repetitions of the amino acid glutamine in disease-specific proteins. In SCA6, polyglutamination occurs in the pore-forming, ion conducting subunit of a voltage-gated calcium channel, the P/Q-type channel. This channel is expressed throughout the brain and is involved in mediating synaptic transmitter release, determining action potential firing frequencies, and contributing to dendritic excitatory potential changes. The channel is in particular highly expressed in Purkinje cells of the cerebellum and is responsible for 90 percent of Ca2+ influx through Ca2+ channels in these cell-types.
One of the hallmarks of the disease is the presence of cytoplasmic and nuclear aggregates in Purkinje cells of SCA6 patients. These aggregates contain the C-terminal protein fragments, including the polyQs of the pore forming subunit of the P/Q-type channel. According to the formation and function of these aggregates, several hypotheses have been suggested. First, the CT-polyQ-containing proteins may constitute a degradation product of the channel that is more stable and therefore enriched in the disease form. Second, the gene encoding the pore-forming subunit may contain a transcription factor with an altered function in the disease form because of the polyQs.
In our studies, we created a mouse model of the SCA6 disease by expressing the C-terminal polyQ-containing protein fragment as found in SCA6 patients, specifically in Purkinje cells 2-3 weeks after the mice are born. These mice develop SCA6-like symptoms after eight month of age. For example, they are ataxic. The ataxia is associated with a change in Purkinje cell firing, which is most likely mediated by the disruption of the interaction of P/Q-type channels with a Ca2+ activated K+ channels. These two channels together regulate the spontaneous firing of Purkinje cells.
Most importantly, the animals developed other problems before movement deficits. In particular, they showed deficits in motor learning. In order to test this we analyzed the eye-blink conditioning of the mice. We presented a tone followed by an air puff onto the eye. Healthy animals learn to close their eyelid when they hear a tone before the air puff is applied. However, animals with the mutated calcium channel fragment could not learn this association. Motor learning in the cerebellum has been suggested to involve long-lasting plasticity changes, such as long-term depression and long-term potentiation) at the Purkinje cell synapses. Indeed, viral-mediated expression of the C-terminal polyQ-containing protein fragment inhibits these forms of long-term plasticity at Purkinje cell synapses.
Since eye blink condition is a noninvasive method, and is easily performed on humans, investigation of changes in the eye blink conditioning has the potential to be used to detect cerebellar mediated diseases during early stages before disease symptoms such as movement deficits become obvious.
M.D. Mark et al. (2015): Spinocerebellar ataxia type 6 protein aggregates cause deficits in motor learning and cerebellar plasticity, The Journal of Neuroscience, DOI: 10.1523/JNEUROSCI.0891-15.2015