A journal article published this week studying sex-linked hormones in brain is the 100th paper describing results from brain tissue provided by the Autism Tissue Program. Taken together, the 100 papers, all published in peer-reviewed scientific journals, represent a huge advance in our understanding of the brains of individuals with autism.
The first publications were released in 2001 and built on existing evidence of developmental changes in the brain of those with autism. The increase to 100 papers in 10 years mirrors the growth of the brain tissue resource from about 20 brains at the start to currently over 100 brains from individuals with a clear diagnosis of autism, ranging in age from 3 to 60. The papers also show the use of a wide range of specialized resources developed by the Autism Tissue Program including MRI, brain tissue biopsies, genetic material from brain tissue and a large permanent brain library of slides all derived from post mortem brains.
The 100th publication is by Valerie Hu, Ph.D. and colleagues at the George Washington University Medical Center titled: ‘Sex hormones in autism: Androgens and estrogens differentially and reciprocally regulate RORA, a novel candidate gene for autism’. The aim of the research, funded in part by Autism Speaks, was to examine a particular sex-linked candidate gene found throughout the human body, including brain tissue. This line of research could provide some rationale for the fact that four times more males are affected with autism than females. Dr. Hu’s research shows that both male and female hormones have varying and significant effects on the activity of the RORA gene product. The RORA gene product regulates an enzyme (aromatase) that converts testosterone into estrogen.
This study offers a molecular mechanism for understanding the sex bias towards males by increasing levels of testosterone. This paper is the first report a sex hormone-responsive candidate gene for ASD. RORA is important for the development of a part of the brain called the cerebellum. The cerebellum is involved in controlling some types of movement, but also plays a role in cognitive tasks such as redirecting attention. RORA also serves to protect neurons against inflammation and oxidative stress.
Dr. Hu and colleagues showed that the female hormone estrogen increases the expression of RORA, while the male hormone androgen (dihydrotestosterone) decreases it. Interestingly, the interaction is somewhat circular as RORA regulates the expression of aromatase, an enzyme that converts testosterone to estrogen. According to Dr. Hu, “We observed in the brains of individuals with autism a link between decreased in activity of RORA and a reduction of aromatase activity. This reduced activity would lead to build up of testosterone and a decrease in estrogen.”
This study provides a molecular explanation for the higher levels of testosterone observed in some individuals with autism. These findings also suggest a mechanism for the male bias in ASD because female brain tissue may benefit from the protective effects of naturally higher levels of estrogen In addition, the estrogen receptor shares some of the same target genes as RORA, thus compensating for RORA deficiency, which the research team has also observed in some individuals with ASD.
Zeroing in on specific gene effects in the brain is one of several research avenues undertaken by scientists that can only be done through the direct examination of human brain tissue. The value of the study of human brain tissue is the interpretation of the data in the context of the current knowledge about autism. Combined with post mortem imaging and genetic analysis scientists can gain a broader and more thorough understanding of ASD.
Scientists studying brain tissue today need to consider disorders that can co-exist with autism. The Autism Tissue Program takes great care to fully document medical conditions of brain donors. The informatics portal catalogs over sixty disorders or conditions occurring in those with a diagnosis of autism including epilepsy, Fragile X, Tuberous Sclerosis Complex, Duschenne Muscular Dystrophy, Angleman, Rett and Asperger Syndromes and partial duplications or deletions of several chromosomes.
The Autism Tissue Program has emerged as an important resource of not only brain tissue but also as in informational hub of research results from an international group of scientists. None of this work would be possible without the dedication of the families who chose to donate brain tissue of loved ones to the Autism Tissue Program. To register you or your family in the brain donor program, please visit www.autismtissueprogram.org for information and online registration, or call 877-333-0999 for information or to initiate a brain donation.
Click here to view the full list of 100 papers the Autism Tissue Program has made possible.