NEK1 mutation found to impair primary cilium function and trigger calcium-dependent intracellular pathogenesis for the first time
HDAC6 inhibitors show therapeutic potential based on newly discovered ALS mechanism
A research team led by Professor Kim Seung-hyun from the Department of Medicine at Hanyang University has identified a new disease mechanism in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. The study revealed that mutations in the NEK1 gene impair the function of primary cilia in neurons and induce neuronal death through calcium-dependent signaling pathways.
The findings were officially published on May 20 in Molecular Neurodegeneration (IF 15.1), a prestigious international journal in the field of neurodegenerative diseases. The research was co-authored by Research Professor Kim Young-eun (Department of Medicine), Research Professor Noh Min-young (Institute for the Integration of Medicine and Innovative Technology), and Professor Oh Sung-il (Kyung Hee University) as first authors. Professor Kim Seung-토토사이트 황토n and Dr. Nam Min-yeop from the Korea Brain Research Institute served as corresponding authors.
ALS is a fatal neurodegenerative disease characterized by the gradual loss of motor neurons, leading to muscle paralysis. To date, its precise pathogenesis remains unclear, and no definitive cure exists. Recently, genetic factors have been identified as significant contributors to ALS, with NEK1 emerging as one of the most notable risk genes worldwide.
Despite this, the specific cellular abnormalities caused by NEK1 mutations had not been fully elucidated, and no prior studies had established a link between NEK1 mutations and defects in primary cilia in neurons.
The research team conducted whole-exome sequencing (WES) on 920 Korean ALS patients and found that 2.5% carried loss-of-function mutations in the NEK1 gene. These patients exhibited faster disease progression and shorter survival periods. By utilizing fibroblasts derived from these patients and iPSC-derived motor neuron (iPSC-MN) models, the team demonstrated that NEK1 deficiency disrupted ciliogenesis, destabilized calcium homeostasis, impaired mitochondrial function, and hindered DNA damage repair—causing extensive pathological changes at the cellular level.
Notably, the team found that treatment with HDAC6 inhibitors reversed cilium damage, mitochondrial dysfunction, cell cycle dysregulation, and neuronal death. This suggests that HDAC6 inhibitors may serve as a viable therapeutic strategy for managing ALS pathophysiology driven by NEK1 mutations.
This study marks the first time that NEK1 mutations have been shown to cause primary cilium dysfunction and calcium-dependent intracellular pathogenesis in ALS. It also presents HDAC6 inhibition as a novel therapeutic avenue. Beyond isolated functional analyses, the research is distinguished by its integrated pathological model that connects cilia, microtubules, mitochondria, and neuronal death using patient-derived fibroblasts and iPSC-based motor neuron models.
These findings are expected to aid in the identification of molecular targets for next-generation ALS treatments, promote drug repositioning strategies involving compounds like HDAC6 inhibitors, and support the development of precision medicine approaches and patient-specific clinical designs for ALS.
The research was supported by the Brain Science Fundamental Technology Development Program under the Source Technology Development Project of the National Research Foundation of Korea, funded by the Ministry of Science and ICT. It was conducted as part of the project “Development of Stress Granule Homeostasis Control Technology Using Small RNAs for Neurodegenerative Proteinopathies” (RS-2023-00265515), with collaboration between Hanyang University Hospital’s Department of Neurology and the Korea Brain Research Institute.