The Cross-Border Biotech Blog

Biotechnology, Health and Business in Canada, the United States and Worldwide

Friday Science Review: March 25, 2011

Beware of Repeats

The Hospital for Sick Children ♦ University of Toronto ♦ Published in PLoS Genetics, Mar. 10, 2011

Trinucleotide repeats are known to be associated with the onset of many diseases including Huntington’s disease and fragile X syndrome. These unstable elements can be transcribed bidirectionally and are dynamic, meaning their numbers can change within individuals and across generations. Particularly worrisome elements include CAG and CTG repeats. In this recent review, Dr. Christopher Pearson describes a process known as Repeat Associated Non-ATG translation (RAN-translation) wherein portions of DNA containing blocks of CAG repeats can be transcribed in the absence of a conventional ATG transcriptional start site. 

Repetitive tracts of DNA can be transcribed in all three reading frames giving rise to RNA transcripts that produce polymeric proteins composed of repeating amino acid building blocks. Unstable repetitive genetic elements may be toxic to the body in several ways, leading to loss-of-protein expression, over-expression of normal proteins, and toxic gain-of-protein function. Due to the functionality of proteins, diseases are often physically manifested at the protein level. Interestingly, when it comes to diseases caused by unstable trinucleotide repeats, RNA transcripts can get in the mix aswell. Transcripts containing repeating CUG or CGG elements can have toxic gain-of-function effects. It is even possible for diseases to be caused through the combined action of a toxic gain-of-function RNA and related toxic polymeric protein.

Acetylcholine, Turning Down the Action

University of Western Ontario ♦ Published in PLoS ONE, Mar. 10, 2011

It has been difficult to assess the contribution that acetylcholine (ACh) has on locomotion. As a major peripheral neurotransmitter it has a vital role in controlling movement, emotional behaviour, and is also involved in memory and learning. Dysfunction in cholinergic activity is involved in the development and onset of many different disorders of the brain, including, but not limited to, Alzheimer’s, schizophrenia, Parkinson’s disease, epilepsy and ADHD. The first attempts at recreating cholinergic dysfunction used non-selective means that were either too destructive, causing destruction of neural types beyond cholinergic, or not destructive enough, failing to eradicate all cholinergic neurons. This short coming left room for significant variation in previous studies, making it difficult to elucidate the effects that ACh has on the various nervous systems.

The alternative to mimicking cholinergic dysfunction was to approach the situation from the standpoint of genetics. This is what Dr. Vania Prado and her lab team have been working on in recent times. This was no easy feat though. To impair cholinergic signaling they chose to target the vesicular acetylcholine transporter (VAChT), a protein that is involved in sequestering acetylcholine and accumulating it within vesicles for transport. The VAChT gene, however, is located within the first intron of the acetylcholine transferase (ChAT) gene in a nested formation. In order to knock down expression of VAChT they flanked it with short “lox” sequences that are used to remove the gene.

What the group found was that the new mutant mice strains they had generated exhibited hyperactivity when exposed to new environments. A similar trait is observed in patients suffering from Alzheimer’s, schizophrenia, and ADHD. Rescuing VAChT expression alleviated that hyperactive phenotype suggesting that acetycholine serves the purpose of toning down the nervous system to control locomotion and other peripheral body functions.

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