Dissecting the molecular mechanisms of ALS pathogenesis

ALS (amyotrophic lateral sclerosis) is a fatal disease caused by motor neuron death, with no effective treatment currently available. It is the most common motor neuron disease in humans, and following Alzheimer's and Parkinson's diseases, the most common neurodegenerative disease. The cellular mechanisms that lead to ALS pathogenesis are not well understood, and their complexity makes developing a viable treatment challenging.
NEK1 is a major ALS gene recently discovered through international collaborations, and mutations in NEK1 have been observed in a significant proportion of patients (5%). In recent years, NEK1 has become an important and popular research focus due to its role in primary cilium morphology and function, as well as in ALS.
Our laboratory is conducting multidisciplinary studies both in vitro and in vivo, using cutting-edge techniques from cell biology, biochemistry, biophysics, proteomics, genetics, and experimental animal models to better understand NEK1 functions; as well as to investigate how NEK1 mutations lead to ALS, with the goal of developing next-generation therapies. In our studies, supported by TÜBİTAK (France-Türkiye bilateral collaboration, 2247A national oustanding researchers program) and EMBO, we have created the first-ever ALS mouse model driven by a NEK1 mutation (Arg812Ter), which mirrors all clinical symptoms seen in ALS patients and dies within 40 weeks. In our in vitro and in vivo studies, we have shown that this mutation produces a truncated, aggregation-prone protein (NEK1t), and that this mutant protein aggregates in motor neurons in the brain and spinal cord, causing toxicity. Importantly, we have developed a pharmacological approach that clears NEK1t from motor neurons by inducing its proteasomal degradation. This treatment, involving interferon alpha (IFN), extends the lifespan of mice by 6 months and alleviates symptoms, representing a world-first discovery (Georgiadou et al., 2024).
Our most recent preliminary data now suggest that NEK1t, in addition to its toxic aggregation propensity, physically interacts with centriolar satellites (CS) and may disrupt their structure and function. CS regulate the biogenesis and function of essential cellular structures such as the centrosome and cilium. CS has been linked to ciliopathies, developmental disorders, and more recently, ALS. In this project, the students are expected to investigate the ALS-related relationship between NEK1t and CS in detail using cell models and our NEK1t ALS mouse model. We hypothesize that NEK1t disrupts CS structure and function, leading to ciliopathy, which contributes to ALS. By doing so, we hope to gain a deeper understanding of both the pathogenesis of ALS caused by NEK1 mutations and the relationship between ALS and ciliopathy. At the translational and clinical levels, drugs targeting CS and cilium function, in combination with IFN, may emerge as novel therapies for ALS.