Analyzing the role of the Calcium Channel Subunit Alpha2delta2 in Axon Regeneration
Funded in: 2016, 2017, 2018
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Problem: Injuries to the adult central nervous system (CNS) often result in permanent disabilities because neurons lose the ability to regenerate their axon.
Target: Gabapentoids in axon growth
Goal: Therapeutic strategy to promote structural plasticity and regeneration following spinal cord injury.
A few classes of adult neurons regenerate their axons under specific conditions as for example DRG neurons. The molecular mechanisms underlying changes in axon growth ability are largely unclear. A better understanding of such mechanisms may help to develop pharmacological strategies to set adult neurons in a growth competent state.
Searching for of regeneration-associated genes by whole transcriptome sequencing and bioinformatic analysis Prof Bradke’s team identified Cacna2d2 as a potential candidate gene. This gene, encoding the Alpha2delta2 subunit of voltage gated calcium channels, acts as a potential gene switch that may limit axon growth and regeneration of sensory neurons in the adult stage.
Indeed, the preliminary results showed that overexpression of Cacna2d2 restrains axon growth, whereas Cacna2d2 gene deletion or silencing promotes axon growth in vitro.
The team hypothesizes that Alpha2delta2 functions as a growth restraint and will analyze now the signaling cascade downstream of Alpha2delta2.
As the anticonvulsant drugs Gabapentin and Pregabalin (PGB) block Alpha2delta1 and Alpha2delta2, the project will test whether PGB
· retains neurons in a growth competent state
· induces axon regeneration in spinal cord injured mice
· induces functional recovery after a spinal cord injury
Additionally, the project will test whether Epothilone treatment in conjunction with PGB treatment could lead to enhanced axon regeneration and functional recovery.
The preliminary data from an observational human study (see here) as well as the preliminary findings of the working group of Dr Bradke suggest that this drug might form a basis for a therapy to promote structural plasticity and regeneration following spinal cord injury.