Issa FA, Mazzochi C, Mock AF, Papazian DM.
Spinocerebellar ataxia type 13 mutant potassium channel alters neuronal excitability and causes locomotor deficits in zebrafish.
J Neurosci. 2011 May 4;31(18):6831-41.
PubMed.
This exciting report by Issa et al. is a critical advance in beginning to understand the essential underlying pathophysiology of SCA13. Though we've known for several years that causative mutations occurred in the KCNC3 voltage-gated potassium channel, this is the first report demonstrating altered neuronal excitability in an animal model of disease. That this effect was characterized in a cell-specific manner and occurred in locomotor behavior provides compelling clues to human disease pathology. This important research begins to lay the groundwork from which we can move away from basic experimental systems and closer to animal physiology and behavior in an effort to understand the fundamental mechanisms of SCA13 in humans pursuant to effective treatments and potential cures.
In this paper by Issa et al., the functional consequence of a mutation in the gene encoding a K-channel (Kv3.3), which is known to cause SCA13 in humans, was studied. SCA13 mutations are not associated with protein aggregation and therefore provide an opportunity to study the link between altered ion channel function and neurodegeneration in the absence of protein aggregation. In zebrafish embryos, in vivo patch-clamp studies revealed that the mutant K-channel suppressed the excitability of fast-firing motor neurons in the spinal cord. This correlated with the observed motor phenotype. The next challenge will be to understand how this neuronal dysfunction induces neurodegeneration and how it can be alleviated.
Comments
University of Florida
This exciting report by Issa et al. is a critical advance in beginning to understand the essential underlying pathophysiology of SCA13. Though we've known for several years that causative mutations occurred in the KCNC3 voltage-gated potassium channel, this is the first report demonstrating altered neuronal excitability in an animal model of disease. That this effect was characterized in a cell-specific manner and occurred in locomotor behavior provides compelling clues to human disease pathology. This important research begins to lay the groundwork from which we can move away from basic experimental systems and closer to animal physiology and behavior in an effort to understand the fundamental mechanisms of SCA13 in humans pursuant to effective treatments and potential cures.
K.U. Leuven and VIB
In this paper by Issa et al., the functional consequence of a mutation in the gene encoding a K-channel (Kv3.3), which is known to cause SCA13 in humans, was studied. SCA13 mutations are not associated with protein aggregation and therefore provide an opportunity to study the link between altered ion channel function and neurodegeneration in the absence of protein aggregation. In zebrafish embryos, in vivo patch-clamp studies revealed that the mutant K-channel suppressed the excitability of fast-firing motor neurons in the spinal cord. This correlated with the observed motor phenotype. The next challenge will be to understand how this neuronal dysfunction induces neurodegeneration and how it can be alleviated.
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