Arpan Mehta's Research Group

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Cell signalling in amyotrophic lateral sclerosis

Arpan Mehta
Arpan Mehta

Solving the black box of ALS involves studying proximal molecular mechanisms
Solving the black box of ALS involves studying proximal molecular mechanisms

Our laboratory studies cell signalling in amyotrophic lateral sclerosis (ALS), a fatal neurological disorder characterised by the degeneration of motor neurons, for which there is still no effective disease-modifying treatment. Genetics has implicated a series of kinases and kinase-regulated proteins in ALS, among them NEK1 and TBK1, yet kinases have had comparatively little dedicated biochemical attention in the field.

NEK1 is a case in point. Rare variants in NEK1 are found in 2–3% of people with ALS and reached exome-wide significance in the largest ALS sequencing study to date. Even so, until recently there was no validated autophosphorylation site, no way to measure the kinase's activity, and few of the antibodies and cell lines needed to study it. A newly found variant could not be classified, and there was no sensible starting point for drug discovery.

Timeline of ALS gene discovery from 1990 to 2020, with gene names in blue and kinase-encoding genes including NEK1 in pink.
ALS genes by year of discovery. Genes in blue encode products that could interact pathologically with kinases; genes in pink encode kinases themselves. NEK1 was identified a decade ago, yet the kinase is termed a ‘dark kinase’ as we still know very little about how it goes awry in motor neuron disease.

What we have found

We mapped NEK1 phosphorylation in cells and found ten recurrent sites. Three of them, pSer14, pThr156 and pSer418, are autophosphorylation sites, which we confirmed with kinase-dead controls, targeted extracted-ion chromatogram analysis, site mutagenesis and phosphospecific antibodies raised in-house.

Phosphorylation of Thr156, in the activation loop, reports how active the kinase is. We used it to test nine ALS-associated missense variants from across the protein. R261C reduced autophosphorylation the most, R232C and A313T reduced it more modestly, and R232H increased it. Structural modelling offers an explanation for each. This is the first activity-based way of classifying NEK1 variants, and it shows that missense variants do not simply behave like the loss of one gene copy.

Domain map of NEK1 showing the kinase domain, basic region, four coiled coils, acidic region and C21ORF2-interaction domain, with three autophosphorylation sites marked above and eight ALS-associated missense variants below.
Domain organisation of NEK1 (isoform 3, 1,286 residues). Orange circles mark the three autophosphorylation sites validated in our Open Biology 2026 paper (pSer14, pThr156 and pSer418); the ringed pThr156, in the activation loop, is the site read out by our phosphospecific antibody. The ALS risk-associated missense variants tested in that paper are shown below the scale.

The NEK1–C21ORF2 complex

NEK1 forms a stable complex with C21ORF2, itself an ALS-associated ciliary and DNA-damage-response protein. Guided by our mass photometry data, we modelled a 2:4 NEK1–C21ORF2 assembly in which an acidic C-terminal face of the NEK1 dimer docks onto a basic N-terminal surface presented by four C21ORF2 chains. The model is a prediction rather than a solved structure, and testing it experimentally is one of our main aims at present.

AlphaFold3 structural model of a predicted complex between two NEK1 molecules and four C21ORF2 molecules, shown as coloured ribbon cartoons above matching electrostatic surface views.
Predicted interface architecture of a putative 2:4 NEK1–C21ORF2 assembly. AlphaFold3 model of two full-length NEK1 chains (light and dark green) and four C21ORF2 chains (dark red, cyan, pink, orange), shown as a cartoon (top) above the corresponding electrostatic surface (bottom; red, acidic; blue, basic). Cross-sectional views show the predominantly acidic C-terminal face of the NEK1 dimer (centre) and the predominantly basic N-terminal surface of the four C21ORF2 chains that docks onto it (right). The 2:4 stoichiometry was informed by mass photometry. This is a predicted model, not an experimentally determined structure. Reproduced from our Open Biology 2026 publication.

Key questions for ongoing work

We are now asking what NEK1 phosphorylates in human motor neurons, and what those substrates do. With Dr Wenting Guo in Strasbourg, we are also running a kinome-wide pooled CRISPR screen in *C9orf72* motor neuron–microglia co-cultures to look for kinases that modify toxicity and could be drugged.

Diagram of a degenerating motor neuron and a box labelled NEK1, with arrows for direct and indirect phosphorylation targets and open questions about other ALS genes and sporadic ALS.
Finding what NEK1 phosphorylates, directly or indirectly, is the step that links the kinase to possible treatments. We also want to know how NEK1 signalling relates to other ALS genes, and whether the same pathway is disturbed in sporadic ALS.

Arpan’s ambition, as a practising clinical neurologist, is to make fundamental discoveries, so that ALS is better understood, better diagnosed and eventually treated.

Joining the group

Arpan is currently applying for intermediate clinician-scientist fellowships to consolidate his work and enable him to build his own team. He is keen to hear from motivated postdoctoral researchers, PhD candidates and clinical trainees considering a research fellowship, who would like to work on kinase signalling in ALS. The laboratory sits in a Unit where all PIs share an ethos that prioritises personal wellbeing and career development, and a positive research culture. Informal enquiries are welcomed via email.

Publications

NEK1 and kinase signalling in ALS

  1. Agarwal S, Abdul Rehman SA, Muñoz IM, Knebel A, Hop PJ, Gourlay R, Brown F, Macartney T, Squires I, Veldink JH, Kenna KP, Rouse J, Mehta AR. NEK1 autophosphorylation is disrupted by amyotrophic lateral sclerosis-associated missense variants: activity biomarkers and structural insights. Open Biol. 2026;16:260209
  2. Agarwal S, Gourlay R, Soares RF, Mehta AR. In-gel tryptic digestion and HCD/EThcD LC-MS/MS for mapping autophosphorylation sites. Bio-protocol. 2026;16(21):e5836.

ALS disease mechanisms in human stem cell models

  1. Mehta AR, Gregory JM, Dando O, Carter RN, Burr K, Nanda J, Story D, McDade K, Smith C, Morton NM, Mahad DJ, Hardingham GE, Chandran S, Selvaraj BT. Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis. Acta Neuropathol. 2021;141:257–279.
  2. Banerjee P, Mehta AR, Nirujogi RS, Cooper J, James OG, Nanda J, Longden J, Burr K, McDade K, Salzinger A, Paza E, Newton J, Story D, Pal S, Smith C, Alessi DR, Selvaraj BT, Priller J, Chandran S. Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration. Sci Adv. 2023;9:eabq0651.
  3. Fumagalli L, Young FL, Boeynaems S, De Decker M, Mehta AR, et al., Van Damme P. C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility. Sci Adv. 2021;7:eabg3013.
  4. Braems E, Bercier V, Van Schoor E, Heeren K, Beckers J, Fumagalli L, Dedeene L, Moisse M, Geudens I, Hersmus N, Mehta AR, et al., Van Den Bosch L. HNRNPK alleviates RNA toxicity by counteracting DNA damage in C9orf72 ALS. Acta Neuropathol. 2022;144:465–488.
  5. Zhao C, Devlin AC, Chouhan AK, Selvaraj BT, Stavrou M, Burr K, Brivio V, He X, Mehta AR, et al., Chandran S. Mutant C9orf72 human iPSC-derived astrocytes cause non-cell autonomous motor neuron pathophysiology. Glia. 2020;68:1046–1064.
  6. Mehta AR, Chandran S, Selvaraj BT. Assessment of mitochondrial trafficking as a surrogate for fast axonal transport in human induced pluripotent stem cell-derived spinal motor neurons. Methods Mol Biol. 2022;2431:311–322.

Clinical trials & trial innovation in ALS

  1. Pal S, Chataway J, Swingler R, Macleod MR, Carragher NO, Hardingham G, Selvaraj BT, Smith C, Wong C, Newton J, Lyle D, Stenson A, Dakin RS, Ihenacho A, Colville S, Mehta AR, et al., Chandran S; MND SMART Investigators. Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND-SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial. Lancet Neurol. 2024;23:1097–1107.
  2. Mehta AR, Carpenter JR, Nicholas JM, Chataway J, Virgo B, Parmar MKB, Chandran S, Pal S. The role of placebo control in clinical trials for neurodegenerative diseases. Nat Med. 2023;29:2682–2683.
  3. Mehta AR, Pal S, Chataway J, Carpenter JR, Parmar MKB, Chandran S. Smarter adaptive platform clinical trials in neurology: a showcase for UK innovation. Brain. 2022;145:e64–e65.
  4. Mehta AR, Chataway J, Pal S, Parmar MKB, Chandran S. Trials for neurodegenerative diseases: time to innovate. Lancet Neurol. 2021;20:984.

ALS genetics, epidemiology and care

  1. Mehta PR, Iacoangeli A, Opie-Martin S, van Vugt JJFA, Al Khleifat A, Bredin A, Ossher L, Andersen PM, Hardiman O, Mehta AR, Fratta P, Talbot K; Project MinE ALS Sequencing Consortium; Al-Chalabi A. The impact of age on genetic testing decisions in amyotrophic lateral sclerosis. Brain. 2022;145:4440–4447.
  2. Glasmacher SA, Kearns PKA, Larraz J, Stirland L, Mehta AR, Newton J, Weir CJ, Chandran S, Pal S; CARE-MND Consortium. Prevalence of multimorbidity and its impact on survival in people with motor neuron disease. Eur J Neurol. 2021;28:2756–2765.
  3. Ng Kee Kwong KC, Gregory JM, Pal S, Chandran S, Mehta AR. Cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis: a systematic review of in vitro studies. Brain Commun. 2020;2:fcaa121.
  4. Mehta AR, Selvaraj BT, Barton SK, McDade K, Abrahams S, Chandran S, Smith C, Gregory JM. Improved detection of RNA foci in C9orf72 amyotrophic lateral sclerosis post-mortem tissue using BaseScope shows a lack of association with cognitive dysfunction. Brain Commun. 2020;2:fcaa009.
  5. Jayaprakash K, Glasmacher SA, Pang B, Beswick E, Mehta AR, Dakin R, Newton J, Chandran S, Pal S; CARE-MND Consortium. Riluzole prescribing, uptake and treatment discontinuation in people with amyotrophic lateral sclerosis in Scotland. J Neurol. 2020;267:2459–2461.

Clinical neurology, global neurology & the culture of neuroscience

  1. Sudarshan R, Sayo AR, Renner DR, de Saram S, Godbole G, Warrell C, Duong HTH, Thwaites CL, Mehta AR*, Coughlan C*. Tetanus: recognition and management. Lancet Infect Dis. 2025;25:e645–e657.
  2. Coughlan C, Sudarshan R, Mehta AR. What comes next for global neurology? Brain. 2026;149:2569–2573.
  3. Devine H, Jabbari E, Scott J, Mehta AR, Dobson R, Mead S. Academic neurology in the UK: a plea to turn away from the precipice. Brain. 2024;147:2270–2273.
  4. Takahashi K, Agarwal S, Mehta AR. 20 years of iPS cells. Lancet Neurol. 2026;25:631.
  5. Mehta AR, Mehta PR, Anderson SP, MacKinnon BLH, Compston A. Grey Matter: Etymology and the neuron(e). Brain. 2020;143:374–379.
  6. Mehta AR, Abbott CM, Chandran S, Haley J. The Cajal Embroidery Project: celebrating neuroscience. Lancet Neurol. 2020;19:979.

* denotes joint senior authorship.

Open science and reagents

Raw mass spectrometry data from the Open Biology paper are deposited in PRIDE (PXD079815) and the analysis files in Zenodo; the paper itself is open access in Open Biology, and the preprint remains on bioRxiv. The reagents are available to any laboratory that asks. Both of the group’s principal methods are published as open protocols (Methods in Molecular Biology, 2022; Bio-protocol, 2026).

Collaborators

Professor Jan Veldink, Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, The Netherlands.

Dr Kevin Kenna, Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, The Netherlands.

Professor Kevin Talbot, Head of Department & Professor of Motor Neuron Biology, University of Oxford.

Professor John Rouse, Professor of Chromosome Biology, Division of Genome Integrity, Faculty of Life Sciences, University of Dundee.

Professor Colin Smith, Director of Centre for Clinical Brain Sciences & Professor of Neuropathology, Euan MacDonald Centre for MND Research, University of Edinburgh.

Dr William Farnaby, Principal Investigator, Centre for Targeted Protein Degradation, Faculty of Life Sciences, University of Dundee.

Dr Wenting Guo, Principal Investigator, NeuroStra Institute, Strasbourg, France.

Dr Raja Nirujogi, Independent Investigator, MRC PPU, Faculty of Life Sciences, University of Dundee.