Molecular Mechanisms: Mutations Make Medley of Symptoms

Spectrum | Autism Research News https://www.spectrumnews.org NEWS Molecular mechanisms: Mutations make medley of symptoms BY JESSICA WRIGHT 23 JANUARY 2013 Protein placement: A mutation in the autism-linked gene CAPS2 causes the protein (right) to accumulate in the cell bodies of neurons instead of travelling down their long projections. Two mutations in CAPS2, an autism-linked protein that promotes neuronal signaling, lead to different autism-like behaviors in mice, according to two studies published in the past two months1, 2. Both mutations have been seen in individuals with autism. CAPS2, also known as CADPS2, promotes the release of chemical messengers at neuronal junctions. These messengers include the growth factor brain-derived neurotrophic factor (BDNF), which has been linked to autism. The CAPS2 gene is within the 7q31, or AUTS1, chromosomal region. One copy of this region is sometimes missing in people with autism. A 2007 study found another autism-linked mutation in CAPS2 called CAPS2-dex3. This mutation leads to a version of the protein that lacks 111 amino acids3. The protein accumulates in the cell bodies of neurons instead of travelling down their long projections. Mice lacking both copies of CAPS2 are less likely than controls to interact with other mice and are more anxious, according to that study. The mice also have altered sleeping patterns and impaired BDNF signaling. 1 / 2 Spectrum | Autism Research News https://www.spectrumnews.org In the first new study, published in the January issue of FEBS Letters, the same team engineered mice lacking only one copy of CAPS2, which better mimics the AUTS1 deletion seen in people. The team also engineered mice that have the CAPS2-dex3 mutation and published their findings in the 18 December issue of the Proceedings of the National Academy of Sciences. Both sets of mice have problems with circadian rhythms and have elevated anxiety. However, mice missing one copy of CAPS2 seem anxious only when exposed to a new object and not in response to bright lights or heights. As pups, these mice also emit fewer vocalizations than controls do. However, in adulthood, only the CAPS2-dex3 mice show social deficits. Neurons from both sets of mice have dampened BDNF release, the studies found. The researchers investigated this further in the CAPS2-dex3 mutation and found that this mutation impairs BDNF transport down neuronal projections. The results show the importance of looking at mutations that are equivalent to those seen in people when making mouse models of autism-linked genes, the researchers say. References: 1: Sadakata T. et al. FEBS Lett. 587, 54-59 (2013) PubMed 2: Sadakata T. et al. Proc. Natl. Acad. Sci. USA 109, 21104-21109 (2012) PubMed 3: Sadakata T. et al. J. Clin. Invest. 117, 931-943 (2007) PubMed 2 / 2 Powered by TCPDF (www.tcpdf.org).

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