The human brain comprises approximately 86 billion neurons whose function is central to human biology. A subset of dopamine neurons die during Parkinson’s disease. Dopamine neurons are also involved in schizophrenia, addiction, learning, and forgetting. How does the human genome program these neurons in health and disease? The BRAINcode project could reveal the answer.
BRAIN Cell encyclOpeDia of transcribed Elements Consortium (BRAINcode), based out of Harvard Medical School, Brigham and Women’s Hospital, and Massachusetts General Hospital, aims to provide a comprehensive map of actively transcribed elements, both protein-coding and non-coding, from specific cell types, directly isolated from human brains of neurologically healthy people and individuals across all stages of Lewy body neuropathology.
Lewy bodies are abnormal aggregates of protein that develop inside nerve cells, associated with Parkinson’s disease (PD), the Lewy body dementias, and some other disorders. They are also seen in cases of multiple system atrophy, a rare, degenerative neurological disorder, particularly the parkinsonian variant.
A recent study from the BRAINcode project team, led by Clemens Scherzer of Harvard Medical School, Boston, USA, was published in the journal Nature Neuroscience. The research employed a strategy going beyond traditional mRNA sequencing. All polyadenylated and non-polyadenylated transcripts over 50 bp were ultra-deeply sequenced using ribo-depleted total RNA from 50,000 neurons laser-captured from more than 100 human post-mortem brains yielding 23 terabytes of reads.
The starting material of 107 high-quality frozen post-mortem human brain samples was sourced from biobanks. These included those housed at the Banner Sun Health Institute, Brain Tissue Center at Massachusetts General Hospital, Harvard Brain Tissue Resource Center at McLean Hospital, University of Kentucky ADC Tissue Bank, University of Maryland Brain and Tissue Bank, Pacific Northwest Dementia and Aging Neuropathology Group (PANDA) at University of Washington Medicine Center, and Neurological Foundation of New Zealand Human Brain Bank.
The study found that, cumulatively, in the neurons, 64.4% of the genome was expressed. 71,022 novel transcribed noncoding elements (TNEs) were discovered, many of which were consistent with active enhancers, responsible for boosting gene expression.
Genetic variants for Parkinson’s disease, schizophrenia, and addiction were enriched in these elements. Expression Quantitative Trait Locus (eQTL) analysis revealed that Parkinson’s disease-associated GWAS variants on chromosome 17q21 regulate the expression of specific enhancer RNAs in dopamine neurons.
The initial phase BRAINcode delineated enhancers active in dopamine neurons as a primary link between genetic variation and neuropsychiatric disease. The BRAINcode project, a generally useful resource for decoding neuropsychiatric disease mechanisms, is available at an easy-to-use web portal (http://www.humanbraincode.org) for evaluating targets for biomarkers and therapeutics in nigral dopamine neurons.