Tuesday, November 12, 2013

Day 4 at #SfN13: Huntington's rats and Parkinson's in a dish

A few years ago I was particularly excited when I heard Sigma-Aldrich was going to produce transgenic rats using zinc finger nuclease technology. When announced, Sigma-Aldrich published on its website that a variety of gene knockouts were already in the plans. These would be knockouts of genes that would likely be of great interest to the research community. Now that this technology has been in the community for awhile, broader genetic tools are being implemented using the laboratory rat—the species of choice for many investigators in neuroscience. Poster # 242.01 by Anthony West of Rosalind Franklin University was an excellent example of this as his study investigated the possibility of therapeutic agents in a rat model of Huntington's rats. The rats in the study were 'equipped' with the human gene that is the causative agent of the devastating condition. In normal individuals, the huntingtin gene contains a certain number of repeats of the codon 'CAG' which encodes glutamine. In affected individuals with Huntington's disease, this codon repeats an aberrant number of these codons and therefore produces an excess of polyglutamine. This study employed a human gene containing 98 CAG repeats (which would cause Huntington's in humans) to study alterations in corticostriatal neurotransmission. Anthony found that in these knock-in rats, the probability of neuronal spiking in striatum was reduced in response to stimulation of motor cortex at low stimulation intensities. Onset to spiking was also delayed in these animals. But, why? According to Anthony, in Huntington's disease, phosphodiesterase activity may be pathologically altered and therefore might be a key target for therapy. Using inhibitors of different phosphodiesterases, Anthony (pictured below) found that inhibition of PDE10A rescued this physiological phenotype in the knock-in rats identifying a putative therapy in this disease.



Anthony West telling me about his exciting work.


Parkinson's disease is another devastating neurodegenerative condition that is under extensive investigation and always has a substantial poster area during the annual meeting. NeuroProof presented an interesting poster (#419.20) on an in vitro model of the disease. As a hallmark of Parkinson's disease, dopaminergic neurons in the substantia nigra undergo degeneration. Models in animals have produced a dearth of information on the possible mechanisms for this action but to date no treatments are available to block or reverse this phenomenon. Additionally, in the event a putative treatment is discovered, the throughput required to evaluate this in a preclinical setting would be necessarily high. However, this would likely be a great challenge (as well as expensive) to evaluate compounds of interest in vivo especially in an academic lab. Using a primary co-culture of neurons and glia placed onto a multielectrode array, neurons were impaired with MPP and rescued with GDNF. What was interesting about this to me, except the obvious large-scale compound testing that could be done with this technology, a variety of electrophysiological outputs were produced from these cultures. This allowed for the rapid visualization of neuronal physiology in a dish and could be an excellent tool for investigators attempting to identify treatments for Parkinson's disease.