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How the HUWE1 protein impacts human intelligence

Brains need just the right balance of "on" and "calm down" signals to produce intellect. Now, scientists show how the HUWE1 protein helps balance nerve cell communication.


Published online in the journal Cell Reports, the results of this study may someday lead to new treatments for intellectual disability or neuro-developmental disorders.

Neuronal cells build the nervous system. In communication between neurons, the brain needs to balance increased transfer of signals (excitatory neurotransmission) with decreased transfer of signals that calm nerve cells down (inhibitory neurotransmissions). Imbalances between these two signal patterns is found in many disorders in neurodevelopment.


"Our study is the first to identify a defect in neuron communication caused by altering the activity of a gene called HUWE1, causing intellectual disability, including Juberg-Marsidi-Brooks syndrome."

Brock Grill PhD, Associate Professor, Department of Neuroscience, The Scripps Research Institute, Florida, USA.


Juberg-Marsidi syndrome is an extremely rare X-linked genetic disorder only completely expressed in boys and men. Women typically have two of the same kind of sexchromosome(XX) — the second X compensating for any damage in the other. Males typically have two distinct sex chromosomes (XY) without any compensating duplicates. Exceptions to these "rules" happen in cases ofXX malesor XY females, with few other variations.

Juberg-Marsidi syndrome is visible at birth, or in the first few weeks of life. Hearing loss, underdeveloped genitals and/or abnormalities of the head, such as an very small head, a face with a flat nasal bridge, eye abnormalities, and sometimes more are exhibited in Juberg-Marsidi. Children have severe mental retardation, with delays in crawling, walking, and general muscle weakness with diminished muscle tone (hypotonia). Because of delayed bone growth, their overall growth is slowed and adults are short. Range and severity of symptoms varies case to case.

To investigate neuronal communication imbalance, Grill and colleagues studied the simple electrical circuit of a transparent, tiny worm known as C. elegans. Despite its small size, this worm shares half its genetic make-up with humans, making it an ideal animal for study of neuronal gene malfunctions as they affect humans.


GABA is the principal inhibiting neurotransmitter in the worm C. elegans — as well as in the human brain. EEL-1 is the protein that regulates GABA in C. elegans. In humans HUWE1 is its equivalent.


Decreasing or increasing the release of GABA changed neuronal signals, creating an imbalance between excited/inhibited signals. This imbalance impaired C. elegans' ability to move, while also creating seizures in the worm.

Brock Grill explains: "Using a simple model circuit, we identified a key player required to achieve balance of excitation and inhibition signals. This opens up a new concept for why HUWE1 causes intellectual disability — as it affects only the release of GABA neurotransmitter, not its level or function."

More research is needed into how the level of GABA actually affects the brain. But, the study increases our understanding of the molecular basis behind intellectual disability. In particular, how a loss of function of HUWE1 impairs nerve cell function and results in mutations causing Juberg-Marsidi-Brooks syndrome.


"The paper is an important step in understanding how increased or decreased activity of HUWE1 can alter circuit function and lead to intellectual disability."

Karla Opperman PhD, TSRI Research Assistant and first author of the study.


Highlights
GABAergic presynaptic transmission is impaired in eel-1 mutants
EEL-1 is required for E/I balance in the worm motor circuit
Locomotion and electroshock responses are abnormal in eel-1 mutants
EEL-1 functions within the RPM-1 signaling pathway to regulate neuronal development

Summary
Genetic changes in the HECT ubiquitin ligase HUWE1 are associated with intellectual disability, but it remains unknown whether HUWE1 functions in post-mitotic neurons to affect circuit function. Using genetics, pharmacology, and electrophysiology, we show that EEL-1, the HUWE1 ortholog in C. elegans, preferentially regulates GABAergic presynaptic transmission. Decreasing or increasing EEL-1 function alters GABAergic transmission and the excitatory/inhibitory (E/I) balance in the worm motor circuit, which leads to impaired locomotion and increased sensitivity to electroshock. Furthermore, multiple mutations associated with intellectual disability impair EEL-1 function. Although synaptic transmission defects did not result from abnormal synapse formation, sensitizing genetic backgrounds revealed that EEL-1 functions in the same pathway as the RING family ubiquitin ligase RPM-1 to regulate synapse formation and axon termination. These findings from a simple model circuit provide insight into the molecular mechanisms required to obtain E/I balance and could have implications for the link between HUWE1 and intellectual disability.

Keywords: EEL-1, HUWE1, intellectual disability, motor neuron, C. elegans, RMP-1, GABA, synaptic transmission, acetylcholine, seizure

In addition to Grill and Opperman, other authors of the study, "The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development," are Andrew Giles and Rayna L. Birnbaum of TSRI; Ben Mulcahy and Mei Zhen of the Lunenfeld-Tannenbaum Research Institute, Mt. Sinai Hospital, Toronto; Monica G. Risley and Ken Dawson-Scully of Florida Atlantic University; and Erik D. Tulgren of the University of Minnesota.

The study was supported by the National Institutes of Health (grant 2R01 NS072129) and the National Science Foundation (grant IOS-1121095). _

About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www.scripps.edu.
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C. elegans is a small soil worm or nematode, that shares a common ancestor with humans.
It lived in the pre-Cambrian era, 500-600 million years ago. Shown above with green
fluorescent protein (gfp) expressed in its neurons, the C. elegans roundworm shares
half of its genetic makeup with humans.
Image Credit:
Erik Lundquist PhD.

 


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