Journal Club: Neuroscience

Graduate Division

NEUROSCIENCE: Intracerebral infusion of antisense oligonucleotides into prion-infected mice. Nazor Friberg, K. et al. (Prusiner). Molecular Therapy Nucleic Acids. 1:e9.

One of the many reasons why prion-based diseases such as mad cow disease are so frightening is that because of the complete lack of therapy, the disease is always fatal. Recently, advances have been made in the development of therapies that might help clear the harmful protein, but there are still significant barriers to development.

Here, members of the Prusiner laboratory at UCSF describe a novel potential treatment strategy using antisense DNA that would decrease expression of the protein that becomes infectiously misfolded, PrP(C).

By decreasing cellular expression of the prion protein at or soon after exposure to the infectious protein (by eating contaminated food, for example), the antisense DNA can prevent the prion from spreading and causing damage to the brain. In a mouse model of infection, intracerebral administration of the DNA soon after infection with prions significantly delayed the onset of disease

NEUROSCIENCE: Intermittent access ethanol consumption dysregulates CRF function in the hypothalamus and is attenuated by the CRF-R1 antagonist, CP-376395. Simms, J.A.; Nielsen, C.K.; Li, R.; Bartlett, S.E. Addiction Biology. January 30. [Epub ahead of print]

Some day in the not-too-distant future, there may be a pharmacological treatment for alcohol use disorders. Recent work has shown that corticotrophin-releasing factor receptor (CRF-R), a mediator of the stress response, is activated with alcohol use – and that inhibition of the CRF-R pathway with a receptor antagonist can significantly reduce the amount and frequency of alcohol self-administration.

Here, researchers explored the side effects of CRF-R inhibition using a novel antagonist, CP-376395. They found that the antagonist significantly decreased alcohol consumption and was associated with decreased receptor signaling in the hypothalamus, providing additional evidence that pharmacological therapies can be used to treat alcohol-use disorders.

NEUROSCIENCE: Function and regulation of AUTS2, a gene implicated in autism and human evolution. Oksenberg, N.; Stevison, L.; Wall, J.D.; Ahituv, N. PLoS Genetics. 9(1):e1003221.

Have you ever wondered what makes us so different from our ill-fated Neanderthal brethren? Much research has been devoted to comparing our respective genetic codes and identifying hotspots where Neanderthals and humans particularly differ.

AUTS2, or Autism susceptibility candidate 2, is one of those hotspots: It’s a gene known to be mutated in some cases of autism and is correlated with many other neurological disorders, such as ADHD and epilepsy.

In some cases, mutations occur in the protein made from the AUTS2 gene, but in many cases, these mutations occur in regions outside the protein-coding part of the gene, known as the “non-coding” region.

Here, researchers characterized the function of AUTS2 protein in a zebra fish model and identified the function of multiple noncoding regions of the gene. They found that without AUTS2, the fish had brain and head abnormalities, and they identified multiple “enhancers” of gene expression in the non-coding regions of the gene.

NEUROSCIENCE: Hypothermia and pharmacological regimens that prevent overexpression and overactivity of the extracellular Calcium-sensing receptor (CaSR) protect neurons against traumatic brain injury. Kim, J.Y.; Kim, N.; Yenari, M.; Chang, W. Journal of Neurotrauma. January 29. [Epub ahead of print]

Traumatic brain injury involves any trauma to the head that causes injury to the brain — for example, a blunt force injury to the head that causes bleeding in the brain. Many times, these injuries, even when resolved, result in some level of permanent brain dysfunction — and the reason why is unknown.

In this paper, researchers investigated the underlying mechanism behind this loss of brain function. They found that following a blunt force impact; neurons in the injured area overexpressed an extracellular calcium-sensing receptor (CaSR) and decreased expression of the inhibitory type B GABA receptor. This was associated with later loss of that brain tissue.

Interestingly, when the researchers blocked CaSR function with the antagonist NPS89636, they found reduced tissue loss and reduced loss of brain function, similar to the protective effects of mild hypothermia (an established protective therapy).

The authors conclude that keeping a balance of inhibitory (GABA) and excitatory (CaSR) receptors helps maintain brain health following acute injury.