Tag Archives: brain behavior

Review: Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models

Neurodegenerative diseases are often associated with accumulation of misfolded proteins. For instance, amyotrophic lateral sclerosis (ALS) affects 5 out of 100000 people worldwide. The most notable ALS cases are Stephen Hawkin and Lou Gehrig, hence the disease is known as Lou Gehrig disease. In 20% of the ALS cases, it is due to a mutation in SOD1, while other cases without Sod1 mutation are associated with TDP-43 protein accumulation in the cytoplasm of spinal cord neurons. This study has shed light on treating ALS by accumulating RNA introns or simply delivering oligonucleotides.

Before you read on: this is a decent paper published in Nature; easy to understand; straight-forward protocols

In this study, the researchers performed a genome wide screen to see which genes are responsible for suppressing TDP-43 toxicity. They narrowed down on dbr1, which suppresses the TDP-43 and TDP-43 mutant toxicity. This suppression is, however, not due to a lowered expression of TDP-43. When human neuronal cell line is transfected with siRNA against dbr1, the toxicity caused by TDP-43 is relieved. The author also proved that Dbr1 knockdown reduces TDP-43 toxicity in primary rat neurons. Using DBR1 mutants that do not have lariat debranching enzymatic activity in yeast spotting assay (look at the figure below if you don’t know what DBR1 does: responsible for debranching the lariat, and subsequently degrading the introns to avoid accumulation of the junk DNA) , TDP-43 toxicity is reduced. As Dbr1 is responsible for debranching lariats following splicing, the knockdown of Dbr1 should increase the amount of introns in the cell. This group incorporated MS2 RNA binding protein into the intron and GFP-tagged MS2-CP protein to visualize the localization of intron. In Dbr1 null cell, intron is colocalized with TDP-43.


The accumulation of introns alleviated the TDP-43 toxicity, which suggest that the accumulation may be a way to treat ALS cases. There are currently no direct therapies against TDP43. So how can we go around this problem? Delivering oligonucleotides into ALS models may be a possible therapy in the near future. In fact, researchers had already used antisense oligonucleotide against SOD1 to treat animal models of ALS which showed slowed disease progression.

Take home message: Without Dbr1, a lariat debranching enzyme, introns accumulate in the cytoplasm which is correlated with lowered TDP-43 toxicity and TDP-43 colocalization with DBR1.

Nat Genet. 2012 Oct 28. doi: 10.1038/ng.2434. [Epub ahead of print]
Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.
Armakola M, Higgins MJ, Figley MD, Barmada SJ, Scarborough EA, Diaz Z, Fang X, Shorter J, Krogan NJ, Finkbeiner S, Farese RV Jr, Gitler AD.

Fight against Multiple Sclerosis: a battle against demyelination

You can take the train to Chicago or you can take the plane to Chicago. So what happens if you somehow make a hybrid model of train and plane (call it trane) to get to Chicago? Do you get there faster or slower? Today, we are going to discuss a neuroscience paper from Hannover, Germany. Demyelination is the loss of myelin sheath in neurons. Myelin sheath is important in conducting signals in the complex neural network. If the myelin sheath is damaged, impairment in movement, coordination is observed. What is an example of demyelination disease? Multiple sclerosis is a prime example – it is one of the most common neurological disorders in youth adults. It is an immune-mediated demyelinating disease in the central nervous system (CNS).

In the paper, the authors ask what happens to the brain if you put two demyelinating agents together. Do you accelerate the process of demyelination?

There are two demyelinating agents tested in this paper: cuprizone and theiler virus. First, cuprizone is a chemical that chelates copper in the central nervous system. This leads to a lack of copper supply to neuronal cells. As copper is required for oligodendrocyte metabolism, oligodendrocytes (responsible for myelination) are dead. Thus, cuprizone leads to the death of oligodendrocytes, which indirectly shuts down the production of myelination. In contrast, theiler virus is a positive sense RNA virus that is grouped under the family of picornaviruses. Theiler virus DA strain causes chronic demyelination. During early phase of infection, the virus replicates in the gray matter of CNS. Later in infection, the virus persists in macrophage. At this stage, the virus induces demyelinating lesion, axonal damage, etc which resemble MS in human.

The paper had done a couple of experiments that support cuprizone in alleviating the CNS demyelination caused by Theiler virus. Cuprizone alone can cause demyelination in a specific region, known as corpus callosum. However, if you put cuprizone with theiler virus, the combination has a reduced demyelination in the thoracic spinal cord comparing to theiler virus infection alone. Look at the figure below, the bottom MBP panel shows you the presence of myelin basic proteins. Myelin basic proteins are responsible for myelination. You can see that there is a dramatic increase of myelin basic proteins in TMEV/CPZ (co-administration) comparing to TMEV (theiler alone). The co-administration also correlates with a better performance on the Rotarod scale (the Rotarod scale: place the mouse on a suspended rotating rod. This enables scientists to test the alertness, balance and the brain function of the mouse). Cuprizone also reduces the detectable amount of immune cells, such as B, T and macrophage during theiler infection. Since the immune system is down, scientists then ask if that allow the virus to replicate faster. The answer is no. In fact, the replication of theiler virus remains the same. This interesting paper has several insights in neuroinflammation. One, the cause of neuroinflammation must be caused by several factors. Two, theiler virus does not require neuroinflammation to remain persistent. Lastly, cuprizone reduces inflammation but does not affect virus replication.

Take home message:

The tug of war between cuprizone and theiler virus does sound fascinating. It is interesting to see if you put two demyelinating agents together, the effect turns out to be less effective than having theiler infection alone. It is hard to say who wins this tug of war, but it is definitely an innovative approach to study neurodegeneration using virus and chemical to induce demyelination.


Cuprizone inhibits demyelinating leukomyelitis by reducing immune responses without virus exacerbation in an infectious model of multiple sclerosis.

Herder V, Hansmann F, Stangel M, Schaudien D, Rohn K, Baumgärtner W, Beineke A.

J Neuroimmunol. 2012 Mar;244(1-2):84-93. Epub 2012 Feb 12.

PMID: 22329906

Spotlight article: Adolescent impulsivity phenotypes characterized by distinct brain networks (Whelan et al 2012)

I read an interesting Nature Neuroscience article by Whelan and colleagues regarding adolescent impulsivity, drug use, and brain networks.  Using functional magnetic resonance imaging, over 1800* 14 year-olds were scanned while performing a stop-signal task (SST).  SST is extensively used as a clinical index of impulse control, where longer SST reaction times indicate less impulse control.  A successful stop trial meant the participant was able to inhibit an already initiated motor response, whereas a failed stop trial meant the participant failed to do so.  Factor analysis revealed multiple different networks for successful stop trials and failed stop trials.

Greater activity in the stop success basal ganglia network and frontal stop success and stop fail networks was found to be correlated with faster SST reaction times.  This suggests that fMRI activity in adolescents with better inhibitory control differs from that in adolescents who are more impulsive.

Impulsive behavior is a known risk factor for drug use in teenagers.  The authors found the stop success orbital network was significantly less active for participants who had misused any substances (alcohol, nicotine, illegal drugs).  After dividing the substance-using group further into subgroups based on usage frequency, this effect was seen even in participants who had only used alcohol four times or less, compared to non-users.  This suggests low orbital network activity could be an fMRI biomarker for potential substance use.  This appears to be a novel conclusion; past literature has demonstrated that the orbitofrontal cortex (OFC) is implicated in drug-seeking behavior and drug use can induce OFC deficits.

Substance misuse & fMRI activity

What struck me was the suggestion that low orbital network activity may predispose a teenager to be more impulsive and thus be at a higher risk for misusing drugs.  I always thought of impulsivity as a personality trait, and it never crossed my mind that even the slightest behavioral differences among non-clinical samples could be reflected in brain activity.  Knowing that the brain is plastic, especially in developmental phases such as adolescence, it makes me wonder if we can alter this personality trait by changing the brain activity.  The next step would be determining if cognitive training or interventions can have beneficial effects on these inhibition networks to potentially decrease the likelihood of substance abuse in adolescents.

*WOW!  This must have been an incredibly expensive study.

Reference: Whelan R et al. Adolescent impulsivity phenotypes characterized by distinct brain networks. Nature Neuroscience 15, 920–925 (2012) doi:10.1038/nn.3092