EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling

ELife
Catrina M LoucksMichel R Leroux

Abstract

Neurons throughout the mammalian brain possess non-motile cilia, organelles with varied functions in sensory physiology and cellular signaling. Yet, the roles of cilia in these neurons are poorly understood. To shed light into their functions, we studied EFHC1, an evolutionarily conserved protein required for motile cilia function and linked to a common form of inherited epilepsy in humans, juvenile myoclonic epilepsy (JME). We demonstrate that C. elegans EFHC-1 functions within specialized non-motile mechanosensory cilia, where it regulates neuronal activation and dopamine signaling. EFHC-1 also localizes at the synapse, where it further modulates dopamine signaling in cooperation with the orthologue of an R-type voltage-gated calcium channel. Our findings unveil a previously undescribed dual-regulation of neuronal excitability at sites of neuronal sensory input (cilium) and neuronal output (synapse). Such a distributed regulatory mechanism may be essential for establishing neuronal activation thresholds under physiological conditions, and when impaired, may represent a novel pathomechanism for epilepsy.

References

Sep 15, 1975·The Journal of Comparative Neurology·J SulstonS Brenner
Feb 12, 1990·Behavioural Brain Research·C H RankinC M Chiba
Nov 1, 1985·Acta Neurologica Scandinavica·D Janz
Jan 1, 1984·Annals of Neurology·A V Delgado-Escueta
Mar 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·J M Kaplan, H R Horvitz
May 1, 1997·Acta Neurologica Scandinavica·S JainM C Maheshwari
Jan 24, 2004·The EMBO Journal·Suparna SanyalHubert H M Van Tol
Jul 20, 2004·Nature Genetics·Toshimitsu SuzukiKazuhiro Yamakawa
Sep 21, 2004·Nature Neuroscience·Daniel L ChaseMichael R Koelle
Jun 25, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Scott L DekenMichael L Nonet
Jan 30, 2007·Epilepsy & Behavior : E&B·Tatiana Frascareli PascalicchioElza Márcia Targas Yacubian
Apr 24, 2007·Nature Neuroscience·Katie S KindtWilliam R Schafer
May 24, 2007·Epilepsy Currents·Antonio V Delgado-Escueta
Oct 11, 2007·The Journal of Comparative Neurology·Georgia A BishopKirk Mykytyn
Dec 21, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Paul W McDonaldRandy D Blakely
Jan 1, 2008·Biochemical and Biophysical Research Communications·Toshimitsu SuzukiKazuhiro Yamakawa
Jul 12, 2008·Methods in Cell Biology·Merav CohenYosef Gruenbaum
Jan 17, 2009·Human Molecular Genetics·Toshimitsu SuzukiKazuhiro Yamakawa
Feb 5, 2009·Journal of Molecular Neuroscience : MN·Fábio F ConteIscia Lopes-Cendes
Sep 1, 2009·Nature Neuroscience·Yasunori Saheki, Cornelia I Bargmann
Sep 8, 2009·Nature Neuroscience·Laurence de NijsBernard Lakaye
Feb 10, 2011·The EMBO Journal·Marina EzcurraWilliam R Schafer
Jun 7, 2011·Nature Methods·Nicholas A SwierczekRex A Kerr
Oct 15, 2011·Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine·Jill C Stoltzfus
Nov 12, 1986·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·J G WhiteS Brenner
May 28, 2013·Current Biology : CB·Ithai RabinowitchWilliam R Schafer
Jul 3, 2013·Nature Methods·Ari E FriedlandJohn A Calarco
Jul 16, 2013·Nature Methods·Eviatar YeminiWilliam R Schafer
Sep 26, 2013·Frontiers in Cellular Neuroscience·Yuri Bozzi, Emiliana Borrelli

❮ Previous
Next ❯

Citations

Oct 25, 2020·International Journal of Molecular Sciences·Sarita ThakranRitushree Kukreti
Apr 24, 2021·Asian Journal of Psychiatry·Dhruva IthalSanjeev Jain

❮ Previous
Next ❯

Methods Mentioned

BETA
transmission electron microscopy
PCR
transgenic

Software Mentioned

ZEN
Matlab
Volocity
IQ1

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.