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A new study has uncovered promising treatment possibilities for neurological disorders linked to CACNA1A gene impairment. The research has shown how CACNA1A haploinsufficiency—when only one copy of the gene functions—disrupts neuron communication, a key factor in conditions like cerebellar ataxia, migraine, and epilepsy. These findings may pave the way for more targeted therapies for patients affected by this gene mutation
The CACNA1A gene encodes a crucial component of calcium channels in the brain, which help regulate electrical signals between neurons. When one copy of this gene is impaired — a condition known as haploinsufficiency — it can lead to significant changes in how brain cells function. Haploinsufficiency of CACNA1A is linked to a wide range of neurological conditions, from cerebellar ataxia to migraine and epilepsy.
Researcher Marina Hommersom investigated how reduced function of the CACNA1A gene disrupts brain cell communication, using a human neuronal cell model. The research group, led by Hans van Bokhoven and Nael Nadif Kasri from the department of Human Genetics, and Bart van de Warrenburg from the department of Neurology, published the results in Brain on October 26, 2024.
To model the effects of CACNA1A haploinsufficiency, they used stem cells derived from humans, which were then carefully engineered into glutamatergic neurons, a type of neuron responsible for excitatory signaling in the brain. These neurons were grown into complex, interconnected networks, to study how they communicate in real-time.
The results showed that CACNA1A-haploinsufficient neurons exhibited altered network synchronization, meaning they did not communicate as smoothly as normal neurons. This altered synchronization was coupled with an increased ability to fire electrical signals in individual neurons, largely due to reduced potassium channel function.
Excitingly, the research showed that a drug already known to be effective in some patients, 4-aminopyridine, was able to partially restore network communication in CACNA1A-haploinsufficient neurons. As a further promising result, an investigational drug that modulates a certain potassium channel type reversed the aberrant firing pattern seen in the neurons, opening up additional avenues for treatment.
Beyond its immediate implications, the study represents a pioneering step in using human-derived stem cell models to explore the wide range of neurological conditions associated with CACNA1A. By bridging patient genetics with real-time cellular models, this research paves the way for developing targeted treatments with a higher degree of predictive accuracy for conditions like ataxia and epilepsy. As these researchers continue to expand on these findings, patients with CACNA1A-related disorders may one day benefit from treatments tailored specifically to the cellular mechanics of their unique genetic profile.
This research is part of Radboudumc Research program: Therapy development for rare disorders of the brain
About the publication
Hommersom MP, Doorn N, Puvogel S, Lewerissa EI, Mordelt A, Ciptasari U, Kampshoff F, Dillen L, van Beusekom E, Oudakker A, Kogo N, Dolga AM, Frega M, Schubert D, van de Warrenburg BPC, Nadif Kasri N, van Bokhoven H. CACNA1A haploinsufficiency leads to reduced synaptic function and increased intrinsic excitability. Brain. 2024 Oct 26:awae330. doi: 10.1093/brain/awae330. Epub ahead of print. PMID: 39460936.
