Study identifies neurogenetics that link abnormal neurodevelopment to ASD.


Autism Spectrum Disorders (ASD) are a group of highly inheritable behavioural disorders. Patients with ASD have mild to severe communication difficulties, repetitive behaviour and social challenges. Such disorders significantly challenge an individual’s ability to conduct daily activities and function normally in society. Currently there are very few medication options that effectively treat ASD with a crucial need to better understand the biology underlying this condition.  Now, a study from researchers at Duke-NUS Medical School and the National Neuroscience Institute has identified a novel mechanism that links abnormal brain development to the cause of ASD. The team state that this new knowledge will help to improve the diagnosis and development of therapeutic interventions for ASD.  The opensource study is published in the journal eLife.

Previous studies show that the neurons that transmit information around the brain develop from cells called neural progenitor cells. These cells can either divide to form more progenitor cells or to become specific types of neurons. If these processes go wrong, a range of neurodevelopmental conditions may develop, including autism spectrum disorder.  It is known that small RNA molecules called microRNAs control gene activity and protein formation by targeting certain other RNA molecules for destruction. One such microRNA, called miR-128, helps newly formed neurons to move to the correct region of the cortex, which is essential for many cognitive processes including thought and language. However, it was not clear whether miR-128 plays any other roles in the development of neurons.  The current study shows how the brain-specific miR-128 plays a key role in causing abnormal brain development.

The current study analysed the role of miR-128 in the developing cortex of mice. Results show that miR-128 prevents cortical neural progenitor cells from dividing and supports their development into more specialized cells. Data findings show that promoting miR-128 to be over-produced in the progenitor cells caused the cells to divide less often and encouraged them to mature into neurons; conversely, removing miR-128 from the progenitor cells caused them to divide more and resulted in fewer neurons forming.

Results show that miR-128 targets a protein called PCM1 that is critical to the cell division of neural precursor cells. The team explain that NPCs during early brain development have two fates, they either stay as NPCs and undergo self-renewal or become neurons through differentiation. Data findings show that the dysfunctional regulation of PCM1 by misregulated miR-128 impairs brain development, which may underlie brain size changes in people with ASD.

The team surmise that their data indicate that miR-128 is an important regulator of neurogenesis in the embryonic cortex and suggests that aberrant miR-128 expression may account for the abnormal cortical development that underlies certain neuropsychiatric disorders, including autism.  For the future, the researchers state that in a separate unpublished study, many new mutations in the PCM1 gene from ASD patients were identified. They now plan to correlate these mutations with functional consequences in brain development with view to increasing the understanding of how autism is caused and enable a more accurate diagnosis of ASD.

Source: Duke-NUS Medical School (Duke-NUS)

 

miR-128 expression in the developing cerebral cortex.   miR-128 expression in the cortex. ISH was performed in an E14.5 mouse embryo brain coronal section with a miR-128 LNA detection probe. The left-side section was probed with a miR scramble control. Scale bars, 50 µm, and 5 µm in the higher magnification image (right-most panel).  MiRNA-128 regulates the proliferation and neurogenesis of neural precursors by targeting PCM1 in the developing cortex.  Zeng et al 2016.

miR-128 expression in the developing cerebral cortex. miR-128 expression in the cortex. ISH was performed in an E14.5 mouse embryo brain coronal section with a miR-128 LNA detection probe. The left-side section was probed with a miR scramble control. Scale bars, 50 µm, and 5 µm in the higher magnification image (right-most panel). MiRNA-128 regulates the proliferation and neurogenesis of neural precursors by targeting PCM1 in the developing cortex. Zeng et al 2016.

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