Another puzzle piece in the autism mystery

Just like in the case of schizophrenia, hundreds of genes have been associated with autistic spectrum disorders (ASDs). Here is another candidate.

97autism - Copy

Féron et al. (2016) reasoned that most of the info we have about the genes that are behaving badly in ASDs comes from studies that used adult cells. Because ASDs are present before or very shortly after birth, they figured that looking for genetic abnormalities in cells that are at the very early stage of ontogenesis might prove to be enlightening. Those cells are stem cells. Of the pluripotent kind. FYI, based on what they can become (a.k.a how potent they are), the stem cells are divided into omipotent, pluripotent, multipotent, oligopotent, and unipotent. So the pluripotents are very ‘potent’ indeed, having the potential of producing a perfect person.

Tongue-twisters aside, the authors’ approach is sensible, albeit non-hypothesis driven. Which means they hadn’t had anything specific in mind when they had started looking for differences in gene expression between the olfactory nasal cells obtained from 11 adult ASDs sufferers and 11 age-matched normal controls. Luckily for them, as transcriptome studies have a tendency to be difficult to replicate, they found the anomalies in the expression of genes that have been already associated with ASD. But, they also found a new one, the MOCOS (MOlybdenum COfactor Sulfurase) gene, which was poorly expressed in ASDs (downregulated, in genetic speak). The enzyme is MOCOS (am I the only one who thinks that MOCOS isolated from nasal cells is too similar to mucus? is the acronym actually a backronym?).

The enzyme is not known to play any role in the nervous system. Therefore, the researchers looked to see where the gene is expressed. Its enzyme could be found all over the brain of both mouse and human. Also, in the intestine, kidneys, and liver. So not much help there.

Next, the authors deleted this gene in a worm, Caenorhabditis elegans, and they found out that the worm’s cells have issues in dealing with oxidative stress (e.g. the toxic effects of free radicals). In addition, their neurons had abnormal synaptic transmission due to problems with vesicular packaging.

Then they managed – with great difficulty – to produce human induced pluripotent cells (iPSCs) in a Petri dish in which the gene MOCOS was partially knocked down. ‘Partially’, because the ‘totally’ did not survive. Which tells us that MOCOS is necessary for survival of iPSCs. The mutant cells had less synaptic buttons than the normal cells, meaning they formed less synapses.

The study, besides identifying a new candidate for diagnosis and treatment, offers some potential explanations for some beguiling data that other studies have brought forth, like the fact that all sorts of neurotransmitter systems seem to be impaired in ADSs, all sorts of brain regions, making very hard to grab the tiger by the tail if the tiger is sprouting a new tail when you look at it, just like the Hydra’s heads. But, discovering a molecule that is involved in an ubiquitous process like synapse formation may provide a way to leave the tiger’s tail(s) alone and focus on the teeth. In the authors’ words:

“As a molecule involved in the formation of dense core vesicles and, further down, neurotransmitter secretion, MOCOS seems to act on the container rather than the content, on the vehicle rather than one of the transported components” (p. 1123).

The knowledge uncovered by this paper makes a very good piece of the ASDs puzzle. Maybe not a corner, but a good edge. Alright, even if it’s not an edge, at least it’s a crucial piece full of details, not one of those sky pieces.

Reference: Féron F, Gepner B, Lacassagne E, Stephan D, Mesnage B, Blanchard MP, Boulanger N, Tardif C, Devèze A, Rousseau S, Suzuki K, Izpisua Belmonte JC, Khrestchatisky M, Nivet E, & Erard-Garcia M (Sep 2016, Epub 4 Aug 2016). Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders. Molecular Psychiatry, 21(9):1215-1224. PMID: 26239292, DOI: 10.1038/mp.2015.106. ARTICLE | FREE FULLTEXT PDF

By Neuronicus, 31 August 2016

Advertisements

Making new neurons from glia. Fully functional, too!

NeuroD1 transforms glial cells into neurons. Summary of the first portion of the Guo et al. (2014) paper.
Fig. 1. NeuroD1 transforms glial cells into neurons. Summary of the first portion of the Guo et al. (2014) paper.

Far more numerous than the neurons, the glial cells have many roles in the brain, one of which is protecting an injury site from being infected. In doing so, they fill up the injury space, but they also prohibit other neurons to grow there.

Guo et al. (2015) managed to turn these glial cells into neurons. Functioning neurons, that is, fully integrated within the rest of the brain network! They did it in a mouse model of stab injury and a mouse model of Alzeihmer’s in vivo. Because a mouse is not a man, they also metamorphosized human astrocytes into functioning glutamatergic neurons in a Petri dish, that is in vitro.

It is an elegant paper that crossed all the Ts and dotted all the Is. They went to a lot of double checking in different ways (see Fig. 1) to make sure their fantastic claim is for real (this kind of double, triple, quadruple checking is what gets a paper into the Big Name journals, like Cell). Needles to say, the findings show a tremendous therapeutic potential for people with central nervous system injuries, like paralyses, strokes, Alzheimer’s, Parkinson’s, Huntington, tumor resections, and many many more. Certainly worth a read!

Reference: Guo Z, Zhang L, Wu Z, Chen Y, Wang F, & Chen G (6 Feb 2014, Epub 19 Dec 2013). In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell, 14(2):188-202. doi: 10.1016/j.stem.2013.12.001. Article | FREE FULLTEXT PDF | Cell cover

By Neuronicus, 18 October 2015