KLHL1

KLHL1 Full Name

kelch-like family member 1

KLHL1 Introduction

KLHL1 is a nervous system-enriched protein named for the multiple copies of Kelch-like repeat domains in the protein. These domains allow KLHL1 to bind to other proteins, including those that organize and regulate the actin cytoskeleton. KLHL1 is broadly, but regionally expressed in the nervous system. For example, in the cerebellar cortex, KLHL1 is highly expressed in the Purkinje cell layer. KLHL1 expression is also observed in other brain regions involved in motor control (striatum, substantia nigra) and in regions more tightly linked to cognitive processes (hippocampus, entorhinal cortex).

With regards to subcellular localization, KLHL1 is a cytoplasmic protein, and the protein's function is likely to be realized through its regulation of the cytoskeleton, which in turn affects neuronal morphology, stability and function. A central physiological function of KLHL1 in neurophysiology is as a regulator of key ion channels. KLHL1 has been shown to directly interact with the α1H subunit of the CaV3.2 channel through its Kelch domain. KLHL1 stabilizes the CaV3.2 protein and facilitates its recycling to the plasma membrane, resulting in an increase in the number of functional channels on the cell surface and ultimately a significant upregulation of neuronal T-type calcium current density. This, as a mechanism, is of fundamental importance in regulating neuronal excitability. For example, in sensory neurons of the dorsal root ganglia (DRG), the level of KLHL1 expression can determine the response threshold of the neuron to mechanical stimulation. A downregulation of KLHL1 expression in these neurons by gene knockout or shRNA interference leads to a reduced density of CaV3.2 channels on the cell membrane and weakened T-type calcium currents. As a result, the mice are abnormally sensitive to mechanical stimuli and show a hyperalgesic phenotype. In hippocampal neurons, KLHL1 knockout can lead to abnormal calcium currents and abnormal synapse number as well. This points to KLHL1, as a regulator of calcium signaling, being broadly involved in advanced brain functions such as synaptic plasticity, neuronal network formation, learning and memory.

The association of KLHL1 with human neurological diseases is most widely recognized in its complex relationship with Spinocerebellar ataxia type 8 (SCA8). SCA8 is an autosomal dominant neurodegenerative disorder. Its pathogenic mechanism is associated with an abnormal expansion of a CTG trinucleotide repeat sequence within the ATXN8OS gene, which is transcribed in the opposite direction and located in the KLHL1 gene locus. This complex gene structure has led to multiple hypotheses regarding the pathogenesis of SCA8, one of which is the "loss-of-function" theory. This theory posits that the CTG expansion may interfere with the normal transcription or translation of the sense-strand KLHL1 gene through some mechanism, leading to decreased levels of the KLHL1 protein. Research in mouse models supports this: mice with Klhl1 gene knockout exhibit motor coordination deficits and cerebellar developmental defects similar to those seen in SCA8 patients, particularly abnormal dendritic morphology in granule cells. This indicates that loss of KLHL1 function is sufficient to trigger ataxia-like pathological phenotypes. However, the pathogenicity of copy number variations (CNVs) in the KLHL1 gene itself, such as large-scale heterozygous deletions or duplications, remains controversial.

Figure 1. SCA8 organization relative to KLHL1. (Source: Mutsuddi M, et al. 2005)

Alternate Names for KLHL1

KLHL1; kelch-like family member 1; MRP2; kelch-like protein 1; Mayven-related protein 2

• 1. Mutsuddi M, et al. Molecular genetics of spinocerebellar ataxia type 8 (SCA8). RNA Biol. 2005 Apr;2(2):49-52.
  2. Gupta VA, et al. Kelch proteins: emerging roles in skeletal muscle development and diseases. Skelet Muscle. 2014 Jun 1;4:11.