Summary: Researchers report they have identified potential treatments that could restore brain function in people on the autism spectrum who lack a gene critical for neural connections.
Source: UT Southwestern.
Scientists have identified a pair of treatments that may restore brain function to autism patients who lack a gene critical to maintaining connections between neurons, according to a study from the Peter O’Donnell Jr. Brain Institute at UT Southwestern Medical Center.
Although this gene has been linked to abnormal brain size, the research in mice demonstrates the gene has no such role and instead is needed to regulate a protein capable of inhibiting the ability of neurons to communicate with each other. Furthermore, the study found that brain connections lost due to absence of the gene can be fully restored within hours by using drugs that block the protein.
“The deletion of this gene impairs brain function in a major way, and we found a way to repair the damage. But we have more work to do before we try these treatments on people. The findings give us a clue as to what pathways are altered and where to look,” said Dr. Craig Powell, Director of Preclinical Research, Director of the Erma Lowe Center for Alzheimer’s Research, and Section Chief of Developmental Brain Disorders in the Department of Neurology & Neurotherapeutics.
The study published in Nature comes amid several recent and ongoing efforts to improve early diagnosis of autism spectrum disorder (ASD) by shifting focus to biological measurements instead of behavioral symptoms. But little is understood about what genes may be effective targets for treatment after a diagnosis is made.
Dr. Powell’s research focused on KCTD13, one of 29 genes in an area of chromosome 16 that is strongly linked to autism, developmental delay, and intellectual disability.
By deleting the gene in mice and measuring various effects, Dr. Powell’s team disproved previous research that indicated KCTD13 deletion caused brain overgrowth commonly seen in people affected by mutations in this chromosomal region. Instead of altering brain size, Kctd13’s absence reduced by half the amount of synaptic connections through which neurons communicate with each other.
Scientists traced the root of the problem to the RhoA protein, which accumulates when Kctd13 is missing. By administering RhoA-inhibiting drugs – either Rhosin or Exoenzyme C3 – Dr. Powell’s laboratory restored brain function in less than four hours.
Exoenzyme C3 is already in human clinical trials for spinal-cord injury – a necessary first step that could speed the process for clinical trials involving autism.
However, Dr. Powell said scientists must first investigate KCTD13’s role in the broader gene pool and study whether improving brain connections can reverse behavioral changes.
“This is an important step, but there is a long road ahead. Now we need to better understand the function of other genes in this chromosomal region and how these may lead to brain dysfunction and the behavioral changes we call autism,” said Dr. Powell, Professor of Neurology & Neurotherapeutics, Neuroscience, and Psychiatry, and holder of the Ed and Sue Rose Distinguished Professorship in Neurology.
Other UT Southwestern collaborators include Drs. Christine Ochoa Escamilla, Irina Filonova, Roopashri Holehonnur, Angela K. Walker, Zhong X. Xuan, Felipe Espinosa, Shunan Liu, Noriyoshi Usui, Haley E. Speed, and Genevieve Konopka, Associate Professor of Neuroscience and the Jon Heighten Scholar in Autism Research.
Funding: Dr. Powell’s study was supported by funding from the National Institute of Child Health and Human Development, The Hartwell Foundation, Autism Science Foundation, Autism Speaks, BRAINS for Autism, and gifts from Debra Caudy and Clay Heighten.
Source: Meghan Rosen – UT Southwestern
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to the researchers.
Original Research: Abstract for “Kctd13 deletion reduces synaptic transmission via increased RhoA” by Christine Ochoa Escamilla, Irina Filonova, Angela K. Walker, Zhong X. Xuan, Roopashri Holehonnur, Felipe Espinosa, Shunan Liu, Summer B. Thyme, Isabel A. López-García, Dorian B. Mendoza, Noriyoshi Usui, Jacob Ellegood, Amelia J. Eisch, Genevieve Konopka, Jason P. Lerch, Alexander F. Schier, Haley E. Speed & Craig M. Powell in Nature. Published online November 1 2017 doi:10.1038/nature24470
Kctd13 deletion reduces synaptic transmission via increased RhoA
Copy-number variants of chromosome 16 region 16p11.2 are linked to neuropsychiatric disorders and are among the most prevalent in autism spectrum disorders. Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes. The function of KCTD13 in the mammalian brain, however, remains unknown. Here we delete the Kctd13 gene in mice and demonstrate reduced synaptic transmission. Reduced synaptic transmission correlates with increased levels of Ras homolog gene family, member A (RhoA), a KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition, suggesting increased RhoA as an important mechanism. In contrast to a previous knockdown study, deletion of Kctd13 or kctd13 does not increase brain size or neurogenesis in mice or zebrafish, respectively. These findings implicate Kctd13 in the regulation of neuronal function relevant to neuropsychiatric disorders and clarify the role of Kctd13 in neurogenesis and brain size. Our data also reveal a potential role for RhoA as a therapeutic target in disorders associated with KCTD13 deletion.
“Kctd13 deletion reduces synaptic transmission via increased RhoA” by Christine Ochoa Escamilla, Irina Filonova, Angela K. Walker, Zhong X. Xuan, Roopashri Holehonnur, Felipe Espinosa, Shunan Liu, Summer B. Thyme, Isabel A. López-García, Dorian B. Mendoza, Noriyoshi Usui, Jacob Ellegood, Amelia J. Eisch, Genevieve Konopka, Jason P. Lerch, Alexander F. Schier, Haley E. Speed & Craig M. Powell in Nature. Published online November 1 2017 doi:10.1038/nature24470