Moritz Mall from the Hector Institute for Translational Brain Research (HITBR) has long been looking into the function of the protein MYT1L in various neuronal illness. The protein is a so-called transcription aspect that decides which genes are active in the cell and which are not. Practically all afferent neuron in the body produce MYT1L throughout their whole life expectancy.
Human brain cells configured from stem cells in the culture meal (red, green). Credit: © Jana Tegethoff/ HITBR
Shopping center had actually currently revealed a couple of years ago that MYT1L secures the identity of nerve cells by suppressing other developmental paths that program a cell toward muscle or connective tissue. Mutations in MYT1L have been found in several neurological illness, such as schizophrenia and epilepsy, but also in brain malformations. In their existing work, which is funded by the European Research Council ERC, Mall and his team analyzed the specific function of the “guardian of neuronal identity” in the development of an ASD. To do this, they genetically turned off MYT1L– both in mice and in human afferent neuron that had actually been stemmed from reprogrammed stem cells in the lab.
The loss of MYT1L led to electrophysiological hyperactivation in mouse and human nerve cells and hence impaired nerve function. Mice lacking MYT1L suffered from brain abnormalities, such as a thinner cortex. The animals also showed several ASS-typical behavioral modifications such as social deficits or hyperactivity.
What was especially striking about the MYT1L-deficient nerve cells was that they produced an excess of salt channels that are generally primarily limited to the heart muscle cells. These pore-shaped proteins allow sodium ions to pass through the cell membrane and are thus vital for electrical conductivity and therefore also for the performance of the cells. Electrophysiological hyperactivation can be the result if a nerve cell produces too many of these channel proteins.
When MYT1L-deficient nerve cells were treated with lamotrigine, their electrophysiological activity returned to normal. In mice, the drug was even able to suppress ASD-associated habits such as hyperactivity.
” Apparently, drug treatment in adulthood can ease brain cell dysfunction and thus counteract the behavioral abnormalities typical of autism– even after the absence of MYT1L has currently impaired brain development throughout the developmental phase of the organism,” describes Moritz Mall. However, the outcomes are still limited to studies in mice; medical studies in patients with disorders from the ASD spectrum have not yet been performed. The very first medical research studies are in the early preparation phase.
Reference: “MYT1L haploinsufficiency in human neurons and mice triggers autism-associated phenotypes that can be reversed by pharmacologic and genetic intervention” by Bettina Weigel, Jana F. Tegethoff, Sarah D. Grieder, Bryce Lim, Bhuvaneswari Nagarajan, Yu-Chao Liu, Jule Truberg, Dimitris Papageorgiou, Juan M. Adrian-Segarra, Laura K. Schmidt, Janina Kaspar, Eric Poisel, Elisa Heinzelmann, Manu Saraswat, Marleen Christ, Christian Arnold, Ignacio L. Ibarra, Joaquin Campos, Jeroen Krijgsveld, Hannah Monyer, Judith B. Zaugg, Claudio Acuna and Moritz Mall, 14 February 2023, Molecular Psychiatry.DOI: 10.1038/ s41380-023-01959-7.
The Hector Institute for Translational Brain Research (HITBR) is a joint organization established by the Central Institute of Mental Health (ZI), the German Cancer Research Center (DKFZ) and the Hector Foundation II. The aim of HITBR is to determine new molecular and practical targets for the therapy of serious psychiatric illness and brain growths.
In a new research study, a drug that blocks sodium channels was shown to suppress autism-associated habits such as hyperactivity in mice. The drug, lamotrigine– sold under the brand Lamictal amongst others– is a medication that is currently utilized to treat epilepsy and stabilize mood in bipolar illness.
If it is genetically switched off in human nerve cells or in mice, the practical changes and signs common of autism occur. A drug that blocks sodium channels in the cell membrane can reverse the effects of MYT1L failure and reduce the functional and behavioral abnormalities in mice.
Disorders from the autism spectrum (ASD, autism spectrum disorders) are not only manifested by disabilities in social interaction, interaction, interest development, and by stereotyped habits patterns. This is typically accompanied by other irregularities such as epilepsy or hyperactivity.
Scientists are intensively searching for the molecular irregularities that contribute to this complex developmental disorder. A wide variety of genetic factors that affect the molecular programs of the nerve cells have already been linked to the advancement of autism.
If it is genetically switched off in human nerve cells or in mice, the practical changes and symptoms typical of autism happen. A drug that obstructs salt channels in the cell membrane can reverse the consequences of MYT1L failure and ease the behavioral and practical abnormalities in mice.
Shopping center had currently shown a few years ago that MYT1L secures the identity of nerve cells by suppressing other developmental pathways that program a cell towards muscle or connective tissue. To do this, they genetically switched off MYT1L– both in mice and in human nerve cells that had been derived from reprogrammed stem cells in the lab.
These pore-shaped proteins allow salt ions to pass through the cell membrane and are thus vital for electrical conductivity and thus also for the functioning of the cells.
