Capturing the spatiotemporal diversity of cellular and molecular mechanisms in ALS

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

ALS is an untreatable and rapidly progressive degeneration of our motor nerves (that allow walking and breathing). In order to develop treatments we must first understand precisely what is going wrong and where. To capture this information, we use skin cells from patients and 'trick' them into becoming stem cells, which are then transformed into motor nerves. We discovered new problems occurring within messages that normally make the building blocks (protein), and also with misplacement and malfunction of these proteins (perhaps due to the 'corrupted' messages). Although it seems logical that the main problem in ALS lies within motor nerves, we and others have now found that actually, the 'supporting' cells called astrocytes are co-conspirators in ALS. Another major aspect of our proposed work is understanding how ageing makes these cells vulnerable to ALS. These studies will help to identify key processes that can then guide new therapy development.

Technical Summary

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive selective degeneration of motor neurons (MNs). We desperately need to understand disease mechanisms to guide effective therapy. The hallmark of ALS (>97% of cases) is a nuclear-to-cytoplasmic mislocalization of an RNA binding protein (TDP43). This implicates two possible disease mechanisms: i) cytoplasmic gain-of-function or ii) nuclear loss of TDP43 function. By developing robust directed differentiation paradigms from hiPSCs, we have identified: i) TDP43 nuclear displacement is a primary event in MNs; ii) aberrant intron retention (IR) is the earliest detectable event in MNs; iii) ALS astrocytes (ACs) lose neuroprotective capacity through impaired EphB1-EphrinB1 JAK-STAT signalling and iv) ageing affects ACs > neurons, shifting their regional identity away from areas of primary neurodegeneration. I now propose to: 1) examine regulation and consequences of aberrant IR in MNs; 2) investigate neuronal-subtype vulnerability by comparing MNs to relatively unaffected dorsal spinal interneurons; 3) elucidate how AC regional identity and reactive status influence their established role in ALS and 4) determine how cellular ageing of MNs and ACs contributes to manifestation of ALS. Triangulating molecular mechanisms, cell-type specific contributions and the impact of cellular ageing will allow us to 'zero' in on salient disease mechanisms.

Planned Impact

The proposed work will lead to results valuable to academics, commercial & private sector businesses, clinicians, ALS patients, the public sector & project staff. Academic beneficiaries were discussed in the previous section.

ALS patients: My partnership to the UK MND association allows this work to be presented to patients on an annual basis, allowing them to see how academic research is progressing. As Clinical Academic Co-Director of the MND service at Queen Square, I can also discuss the research with patients (who often ask this question).

Public sector: Through our lab's clear commitment to public engagement, we will increase public awareness of ALS.

Staff: New staff recruited will be trained in the application of RNAseq; a powerful yet non-trivial technology that has many applications in both academia, healthcare and the pharmaceutical sector. Staff will be able to transfer their experience into (and cross-fertilise) diverse career destinations following project completion (including different laboratories, teaching positions and industry).

Commercial & private sector businesses: Cell-type specific molecular understanding of pathomechanisms of ALS will provide important new insights and possibly new targets for the commercial sector developing ALS treatments. I have established collaborations with Takeda pharmaceuticals, Cerevance Ltd and Ono Pharmaceuticals. I also leas a lab at the Crick Institute where GlaxoSmithKline have a physical presence aimed at strengthening partnerships between academia and the pharmaceutical industry. Both avenues will present opportunities to discuss findings with individuals who have the 'nous' in both drug development & medicinal chemistry. This would accelerate any potential for the clinical translation of this proposed work.

Clinicians: Publication of our findings will increase knowledge of the timeline of ALS transcriptional events, & is expected to be of interest/use to clinical colleagues. Understanding which pathways are perturbed earlier in the disease may uncover new cellular and/or molecular targets for further exploration.
 
Title Image-based deep learning reveals the responses of human motor neurons to stress and VCP-related ALS 
Description The aim of the study was to investigate relationships between ALS-related RNA-binding proteins and ALS, under different stress conditions. 
Type Of Art Image 
Year Produced 2021 
URL https://idr.openmicroscopy.org/webclient/?show=screen-3001
 
Description Education - Public Engagement (see dedicated section for detailed examples)
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description International 3Rs Prize 2018 - please see awards section for details of impact
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Invited to a roundtable discussion in Parliament by Steve Barclay, Secretary of State for Health
Geographic Reach National 
Policy Influence Type Participation in a guidance/advisory committee
Impact Round table on motor neurone disease (MND) research on Thursday 2nd February which provided the opportunity to discuss how we can accelerate the path towards developing treatments for MND - specifically how the £50M promised by the government to ALS research will actually be operationalised
 
Description Capturing the spatiotemporal diversity of cellular and molecular mechanisms in ALS
Amount £1,885,121 (GBP)
Funding ID MR/S006591/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 12/2018 
End 11/2023
 
Description Capturing the spatiotemporal diversity of cellular and molecular mechanisms in ALS
Amount £150,000 (GBP)
Funding ID Patani/Nov18/950-795 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2019 
End 02/2024
 
Description Studying the Neuromuscular Junction in ALS
Amount £73,500 (GBP)
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2018 
End 11/2021
 
Title Directed differentiation of hiPSCs to highly enriched spinal cord motor neurons and astrocytes 
Description First, we established an innovative ontogeny-recapitulating method for motor neurogenesis from human iPSCs. Specifically, we established amongst the most reproducible, highly enriched, time-efficient and robustly characterized directed differentiation paradigms of human iPSCs to both spinal cord motor neurons and astrocytes. We routinely achieve >90% of our target cell population. We have extensively characterized these cultures with stage-specific molecular profiling (RNAseq, qPCR and immunocytochemistry) and functional assays (responses to physiological calcium stimuli: KCl and glutamate, patch clamping, multi-electrode array). We have also generated highly enriched region-specific ACs with similar rigour and routinely culture >90% enriched spinal astrocytes. These have undergone extensive characterization as above, including RNAseq and immunocytochemistry) and express >90% GLAST, GLT-1, GFAP and ALDH1L1. Furthermore, we have functionally characterized these astrocytes as follows: calcium responses to physiological calcium stimuli (ATP). These platforms allow confident investigation of developmental stage-specific phenotypes of ALS motor neurons and astrocytes. This is the first study that carefully chronicles sequential pathogenic events in motor neurons. The primary event is TDP-43 nuclear loss, which coincides with endoplasmic reticulum (ER) stress. We have verified ER stress using a number of approaches (western blotting for BiP and phosphorylated eIF2a, tunicamycin stress assay, electron microscopy showing dilatation of ER, increased mitochondrial-ER contacts, ER calcium store assay, RNAseq showing a signature for translational arrest). Secondary pathogenic events include mitochondrial depolarisation, oxidative stress, synaptic loss, electrical hypoactivity (less frequent 'bursting' activity and less coordinated busting activity in neuronal networks) and ultimately motor neuron death. Indeed we confirmed a robust cell death phenotype in ALS motor neurons using 4 orthogonal approaches (propidium iodide assay, nuclear pyknosis, activated caspase 3 and longitudinal survival analysis). We also found that ALS astrocytes exhibit a clear survival phenotype in longitudinal imaging studies. Furthermore, they fail to support survival of motor neurons compared to their wildtype counterparts. Together these data suggest both cell autonomous and non cell autonomous mechanisms of ALS. Furthermore, our work clearly highlights the value of the iPSC platform in faithfully recapitulating key aspects of ALS pathobiology and allowing investigation of cellular autonomy with fidelity and precision. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2017 
Provided To Others? Yes  
Impact The main impact of this work is to demonstrate the ability of an arguably more physiological system (human, bypasses the need to over express knock down or knock out) that can at least reduce if not in some cases replace animal models. Given this ability to capture authentic phenotypes in a human experimental platform and carefully resolve issues of cellular autonomy, this work has inspired several groups to collaborate with us and use our model to complement, reduce or replace their animal work. The ability to study human target cell types in high enrichment and conduct time-resolved investigations is unprecedented until the advent of iPSC biology. A major hurdle in this area is the expertise to predictably manipulate cell fate using developmental cues. My group has invested considerable effort into developing highly robust, cost- and time-effective methods to generate a variety of clinically relevant cell types for the study of neurodegeneration. Direct examples of how my group's work has impacted this research area beyond our primary work includes i) Adrian Isaac's Lab at UCL (Simone et al EMBO Molecular Medicine 2018), now has a focus on iPSCs rather than animal models; ii) Andras Lakatos' Lab in Cambridge (Tyzack et al Nature Communications 2017), again now has a clear emphasis on iPSC-based models, which formed part of his successful MRC clinician scientist award; iii) David Rowitch's lab (David is a world-renowned leader in glial biology) collaborated with us for our iPSC-astrocyte model, which complemented his primary work (Kelley et al Neuron 2018). These few examples of investigators that have seen their primary data validated in iPSC models has motivated them to invest in this area, which will inevitably reduce and eventually possibly replace animal work. The reason that they initiated collaboration is due to the robustness of our iPSC differentiation paradigms and disease models Animal models have provided significant insight into basic and applied neuroscience, however, they have not directly yielded an impactful therapy for neurodegeneration. Furthermore, there is increasing recognition of key interspecies differences between mouse and man (at anatomical, cellular, molecular, circuit and functional levels). Therefore, it is my vision that this phase of cross-validation in iPSC models will increase recognition of their clear utility as a robust disease model with several unparalleled advantages. It is my strong belief that this will be followed by a future phase where iPSCs are indeed utilized as a primary discovery model and a primary pre-clinical model (including drug discovery and toxicity screening in relevant cell types). I sincerely believe that such a re-prioritisation would yield a step change in our translational yield. It is possible of course that some limited in vivo validation studies may be needed but by placing these as a secondary validation for a more focussed experiment, it would significantly reduce the number of animals required per study. This vision is strengthened by recent studies that demonstrate that 2 drugs failing clinical trials in ALS (Dexpramipexole and Olesoxime), also failed to show benefit when retroactively tested in hiPSCs. Furthermore, a screen on hiPSCs in the same study led to the discovery that a dual kinase inhibitor called Kenpaullone is effective and this has now entered clinical trials (Lee Rubin's Lab in Harvard). Likewise, after many failed trials based on the SOD1 mouse model, an iPSC based study discovered a heightened basal excitability, which in turn led to the discovery of Retigabine as a disease modifying agent Derivatives of Retigabine have entered clinical trials (Kevin Eggan's Lab in Harvard). I have been working with iPSCs for 12 years and am utterly committed to the 3Rs. Human induced pluripotent stem cells can have broad ranging impacts in the following: 1) The study of human development 2) The study of human diseases (including the study of cellular autonomy through monoculture or co- culture paradigms; 2D and 3D) 3) Drug screening 4) Toxicity screening Harnessing hiPSC technology for each of these research areas would significantly impact on the necessity for / extent of animal work. A crucial first step is to invest in the directed differentiation paradigms that allow diverse cell types to be made, each in high enrichment. These can then be used to validate key phenotypes in the relevant disease area (e.g. rhythm disturbances in cardiac muscle cells or drug-related toxicity of hepatic cells). Such efforts will generate 'buy in' from research groups and will push for reprioritisation of approaches to modelling disease, emphasising human iPSC-based approaches rather than animal models. Indeed, I have engaged strongly with pharmaceutical companies in this regard (Takeda, Ono, Calico, MSD, IONIS) and have really pushed this agenda based on our robust data. Indeed, these companies are excited to work with our models for high throughput screening and we have historically secured 3 project grants from them that are purely hiPSC-based (and are in advanced negotiations over 3 further grants). Such industry collaborations can amplify the message about the utility of these models over and above transgenic animals. We have disseminated our findings through publications in open access journals. We also present our work at local, national and international conferences. We are equally committed to communicating our research effectively to non-scientists, as evidence by our public engagement strategy / portfolio: Our vision is to use innovative and impactful engagement to i) foster a genuine dialogue between science and society ii) inspire the next generation of thinkers and leaders and iii) engagement throughout the research lif cycle. Some examples of our work: i) 'Action Potential', where professional dancers 'anthropomorphise' an action potential arriving at a neuromuscular Junction. This idea was conceived and operationalized by myself through forming key collaborations with MNDA and Combination Dance. Initial fundingfor this activity from my Wellcome Public Engagement Grant has been matched by external funding and this has been performed at 6 venues including the Science Museum, Imperial Science Festival (Great Hall) and UCL's Bloomsbury theatre. ii) Thought to Flesh dramatizes the emotions of a patient with MND. This has been performed at 3 different venues (initial funding matched following the premiere at the Vault Festival in Waterloo). Subsequently performed at UCL'd 'It's all academic' festival and Clapham Grand. Sponsored recently by Pint of Science and Creative Reactions. I conceived this idea together with Gareth Mitchell and Nathalie Czarneski. iii) Social media. Our lab has >1000 followers on twitter (@PataniLab). We have a facebook page and a UCL website. A private website has also been developed: http://thepatanilab.com. iv) Video blogs or 'Vlogs': Our lab collaborates with a video producer and made several short videos to demystify science and build a trusting bridge between researchers and society. We have these videos publicly available on our lab's YouTube channel: https://m.youtube.com/channel/UCTlFRpR7KsdOC2dX1lkFXxA 
URL https://m.youtube.com/channel/UCTlFRpR7KsdOC2dX1lkFXxA
 
Title An aberrant cytoplasmic intron retention programme is a blueprint for ALS-related RBP mislocalization 
Description We generated high-throughput poly(A) RNA-seq data with high coverage derived from nuclear and cytoplasmic fractions of human induced pluripotent stem cells (hiPSC; day 0), neural precursors (NPC; day 3 and day 7), 'patterned' precursor motor neurons (ventral spinal cord; pMN; day 14), post-mitotic but electrophysiologically immature motor neurons (MN; day 22), and electrophysiologically mature MNs (mMNs; day 35). The cellular material was derived from two patients with the ALS-causing VCP gene mutation and four healthy controls (Fig. 1A; 95 samples from 6 time-points and 3 genotypes; 4 clones from 4 different healthy controls and 3 clones from 2 ALS patients with VCP mutations: R155C and R191Q, hereafter termed VCPmu). All sequence data for this project has been deposited at NCBI GEO database under accession number GSE152983. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact Intron retention is known to regulate gene expression. We recently described intron retention as the predominant splicing programme characterizing early stages of motor neurogenesis from human induced pluripotent stem cells (hiPSCs) and it's perturbation in familial amyotrophic lateral sclerosis (ALS). Here, we sought to gain more insight into the nucleocytoplasmic distribution of aberrant intron-retaining transcripts (IRTs) and to identify their discriminating molecular features. We combined cellular fractionation with hiPSCs undergoing motor neurogenesis and deep-sequenced 95 samples: ALS vs control hiPSCs and nuclear vs cytoplasmic compartments across six timepoints, which represents a rich transcriptomic resource for basic and applied neuroscientists. Using this resource, we identified >100 aberrant cytoplasmic IRTs in cultures carrying ALS-causing VCP gene mutations. We taxonomized aberrant IRTs by their nucleocytoplasmic distribution and demonstrate that these classes exhibit sequence-specific attributes and differential predicted binding affinity to ALS-related RNA binding proteins. In summary we uncover a distinct class of cytoplasmic IRTs that serve as 'blueprints' for established molecular hallmarks of ALS (nuclear-to-cytoplasmic mislocalisation of TDP-43, SFPQ and FUS) and therefore may also represent therapeutic targets. 
URL https://www.biorxiv.org/content/10.1101/2020.07.20.211557v1.full.pdf
 
Title Automated and unbiased discrimination of ALS from control tissue at single cell resolution 
Description We provide raw images and complete source code (which is not a software but rather a compilation of R and py-thon) to readily reproduce figures, tables, and other results that involve computation in order to facilitate the development and evaluation of additional profiling methods. We also provide the measurements of each of the ~600 cells whose origins are annotated. The raw im-ages, metadata and single-cell measurements provided as comma-delimited files have been deposited Zenodo under the accession number 3985099, together with the image processing pipelines. The scripts for automated detection of MNS subpopulation can be freely accessed on Github in the following repository: https://github.com/RLuis ier/ALSdi sMNs. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact we tested different machine learning methods to analyse high-content microscopy measurements of hundreds of motor neurons (MNs) from amyotrophic lateral sclerosis (ALS) post-mortem tissue sections. Furthermore, we automated the identification of phenotypically distinct MN subpopulations in VCP- and SOD1-mutant transgenic mice, revealing common morphological cellular phenotypes. Additionally we established scoring met-rics to rank cells and tissue samples for both disease probability and severity. By adapting this paradigm to human post-mortem tissue, we validated our core finding that morphological descriptors robustly discriminate ALS from control healthy tissue at single cell resolution. Determining disease presence, severity and unbiased phenotypes at single cell resolution might prove transformational in our understanding of ALS and neurodegeneration more broadly. 
 
Title Reactive astrocytes in ALS display diminished intron retention 
Description Deep RNA seq, mass spec of hiPSC-derived astrocytes (and code) for project: Reactive astrocytes in ALS display diminished intron retention All raw and processed mRNA sequencing data generated in this study have been deposited in the NCBI Sequence Read Archive (BioProject Gene Expression Omnibus) un- der accession number GSE160133. RAW Mass Spectrome- try data have been deposited to the ProteomeXchange Con- sortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository with the dataset identifier PXD022604. Code is available through GitHub https:// github.com/ojziff/ALS astrocyte intron retention. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact Reactive astrocytes are implicated in amyotrophic lateral sclerosis (ALS), although the mechanisms controlling reactive transformation are unknown. We show that decreased intron retention (IR) is common to human-induced pluripotent stem cell (hiPSC)- derived astrocytes carrying ALS-causing mutations in VCP, SOD1 and C9orf72. Notably, transcripts with decreased IR and increased expression are overrep- resented in reactivity processes including cell adhe- sion, stress response and immune activation. This was recapitulated in public-datasets for (i) hiPSC- derived astrocytes stimulated with cytokines to undergo reactive transformation and (ii) in vivo astro- cytes following selective deletion of TDP-43. We also re-examined public translatome sequencing (TRAP- seq) of astrocytes from a SOD1 mouse model, which revealed that transcripts upregulated in translation significantly overlap with transcripts exhibiting de- creased IR. Using nucleocytoplasmic fractionation of VCP mutant astrocytes coupled with mRNA sequenc- ing and proteomics, we identify that decreased IR in nuclear transcripts is associated with enhanced non- sense mediated decay and increased cytoplasmic ex- pression of transcripts and proteins regulating re- active transformation. These findings are consis- tent with a molecular model for reactive transforma- tion in astrocytes whereby poised nuclear reactivity- related IR transcripts are spliced, undergo nuclear- to-cytoplasmic translocation and translation. Our study therefore provides new insights into the molec- ular regulation of reactive transformation in astro- cytes. 
 
Description DNA damage in ALS 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Simon Boulton, FRS FMedSci leader in DNA damage and out team have uncovered DNA damage as a hallmark in ALS
Collaborator Contribution DNA damage expertise. Now following us with new functional genomic methods developed in the Boulton Lab
Impact Integrated analysis of ALS links genome instability to TDP-43 pathology - Accepted in Nature Communications
Start Year 2022
 
Description RNA dysregulation in ALS 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Myself: I am a Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, a top 3 hospital worldwide for neurological treatment. My clinical expertise is in ALS diagnosis and treatment, and co-directs clinical service. My scientific research focuses on developing human iPSC models for ALS that display reliable pathogenic phenotypes; our laboratory is one of the few internationally that produces robust cultures of both motor neurons and astrocytes. We have deeply characterised our cultures Our research is co-located at the Francis Crick Institute, UK's flagship center for basic biomedical research. Crick provides advanced core facilities ranging from scientific computing and sequencing to gene-editing and high-throughput screening. We have an outstanding track-record of collaboration: Ule and Patani have also collaborated for >10 years, exploring the impact of RNA-processing in neural development and ALS. In 2017, the three of us published a study characterizing robust phenotypes in ALS motor neurons and astrocytes (Hall et al Cell Reports 2017); this directly led to our current collaborative discovery of aberrant intron retention in ALS (Luisier et al Nature Communications in 2018 and later recognised by the Paulo Gontigo International Prize in Medicine 2018). I provide the ALS disease platform, including patient-derived iPSC, post-mortem samples, and mouse models. As an active neurologist, I will ultimately take molecular findings to the clinic, accessing consented patient material; he has industry partnerships (including Takeda, Cerevance and Ono), so we are poised to translate mechanistic insights from this project into drug discovery.
Collaborator Contribution Jernej Ule is Professor of Molecular Neurobiology; he pioneered CLIP techniques and has applied them to study RNAs bound by ALS-associated proteins, including TDP43 and FUS. Ule provides the expertise for the molecular work, splicing perturbations, CLIP and proteomic experiments. Nicholas Luscombe is Professor of Computational Biology studying transcriptional and post-transcriptional regulation and their use in controlling biological processes such as development; he performs detailed statistical analyses of large-scale datasets to decode the information contained in genome sequences. Luscombe performs all the computational analysis to build statistical models, integrating both primary and publicly available genomic datasets, as well as imaging data from the cellular experiments. Study designs arise from continuous discussions between us; colocation means that fresh insights are iteratively cycled between discovery, interpretation and planning with minimal delay.
Impact Grants MRC Senior Clinical Fellowship awarded in 2018 Prizes 03/19 International 3Rs Prize for 2018 09/18 International Paulo Gontijo Prize in Medicine for 2018 06/16 Faculty of Brain Sciences (UCL) Excellence Award in Scientific Communication Publications: 1. Smethurst P, Risse E, Tyzack G, Mitchell JS, Taha DM, Chen Y, Newcombe J, Collinge, Sidle K*, Patani R*. Distinct responses of neurons and astrocytes to TDP-43 proteinopathy in amyotrophic lateral sclerosis. Brain. In Press (Corresponding author). 2. Pandya VA, Patani R*. Decoding the relationship between ageing and amyotrophic lateral sclerosis: a cellular perspective. Brain. 2019 Dec 18. pii: awz360. doi: 10.1093/brain/awz360. (Corresponding author). 3. Thelin EP, Hall CE, Tyzack GE, Frostell A, Giorgi-Coll S, Alam A, Carpenter KLH, Mitchell J, Tajsic T, Hutchinson PJ, Patani R*, Helmy A*. Delineating Astrocytic Cytokine Responses in a Human Stem Cell Model of Neural Trauma. J Neurotrauma. 2019 Sep 18. doi: 10.1089/neu.2019.6480. (Corresponding author). 4. Tyzack GE, Luisier R, Taha DM, Neeves J, Modic M, Mitchell JS, Meyer I, Greensmith L, Newcombe J, Ule J, Luscombe NM*, Patani R*. Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis. Brain. 2019 Sep 1;142(9):2572-2580. doi: 10.1093/brain/awz217. (Corresponding author). 5. Malik B, Devine H, Patani R, La Spada AR, Hanna MG, Greensmith L. Gene expression analysis reveals early dysregulation of disease pathways and links Chmp7 to pathogenesis of spinal and bulbar muscular atrophy. Sci Rep. 2019 Mar 5;9(1):3539. doi: 10.1038/s41598-019-40118-3. 5. Ziff OJ, Patani R*. Harnessing cellular aging in human stem cell models of amyotrophic lateral sclerosis. Aging Cell. 2018 e12862. 6. Luisier R, Tyzack GE, Hall CE, Mitchell JS, Devine H, Taha DM, Malik B, Meyer I, Greensmith L, Newcombe J, Ule J, Luscombe NM*, Patani R*. Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS. Nature Communications. 2018 May 22;9(1):2010. (Corresponding author). 7. Peskett TR, Rau F, O'Driscoll J, Patani R, Lowe R, Saibil HR. A liquid to solid phase transition underlying pathological huntingtin exon1 aggregation. Molecular Cell. 2018 May 17;70(4):588-601.e6. 8. Maffioletti SM, Sarcar S, Henderson ABH, Mannhardt I, Pinton L, Moyle LA, Steele-Stallard H, Cappellari O, Wells KE, Ferrari G, Mitchell JS, Tyzack GE, Kotiadis VN, Khedr M, Ragazzi M, Wang W, Duchen MR, Patani R, Zammit PS, Wells DJ, Eschenhagen T, Tedesco FS.Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering. Cell Reports. 2018 Apr 17;23(3):899-908. 9. Kelley KW, Ben Haim L, Schirmer L, Tyzack GE, Tolman M, Miller JG, Tsai HH, Chang SM, Molofsky AV, Yang Y, Patani R, Lakatos A, Ullian EM, Rowitch DH.Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength. Neuron. 2018 Apr 18;98(2):306-319.e7. 10. Serio A, Patani R*. Concise Review: The Cellular Conspiracy of Amyotrophic Lateral Sclerosis. Stem Cells. 2018 Mar;36(3):293-303. 11. R. Simone, Balendra R, Moens TG, Preza E, Wilson KM, Heslegrave A, Jaramillo JG, Abdelkarim S, Clarke M, Woodling NS.... Patani R*, Fratta P*, Isaacs AM*. 'G-quadruplex- binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo'. EMBO Molecular Medicine. 2018 Jan;10(1):22-31. (joint senior and corresponding author). 12. Tyzack GE, Hall CE, Sibley CR, Cymes T, Forostyak S, Carlino G, Meyer I, Schiavo G, Zhang SC, Gibbons GM, Newcombe J, Patani R*, Lakatos A* 'EphB1 is a neuronal signal that induces a neuroprotective astrocyte state, but fails in ALS' Nature Communications 2017 Oct 27;8(1):1164. (*Joint senior and corresponding author). 13. Thelin EP, Hall CE, Gupta K, Carpenter KLH, Chandran S, Hutchinson PJ, Patani R*, Helmy A*. Elucidating pro-inflammatory cytokine responses following traumatic brain injury in a human stem cell model.Journal of Neurotrauma 2017 Oct 5. doi: 10.1089/neu.2017.5155. (*Joint senior and corresponding author). 14. Hall CE, Yao Z, Choi M, Tyzack GE, Serio A, Luisier R, Harley J, Preza E, Arber C, Crisp SJ, Watson PMD, Kullmann DM, Abramov AY, Wray S, Burley R, Loh SHY, Martins LM, Stevens MM, Luscombe NM, Sibley C, Lakatos A, Ule J, Gandhi S*, Patani R*. 'Progressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS'. Cell Reports 2017 May 30;19(9):1739-1749. (Corresponding author). 15. Soreq L, UK Brain Expression Consortium, North American Brain Expression Consortium, Rose J, Soreq E, Hardy J, Trabzuni D, Cookson MR, Smith C, Ryten M, Patani R*, Ule J*. 'Major shifts in glial regional identity are a transcriptional hallmark of human brain aging'. Cell Reports 2017 Jan 10;18(2):557-570. (*Joint senior and corresponding author). 12. Devine H, Patani R. 'The Translational Potential of Human Induced Pluripotent Stem Cells for Clinical Neurology'. Cell Biology and Toxicology 2017 Apr;33(2):129-144. 16. Smethurst P, Newcombe J, Troakes C, Simone R, Chen YR, Patani R, Sidle K. 'In vitro prion-like behaviour of TDP-43 in ALS'. Neurobiol Dis. 2016 S0969-9961(16)30195-4. 17. Tyzack G, Lakatos A, Patani R. 'Human Stem Cell-Derived Astrocytes: Specification and Relevance for Neurological Disorders'. Current Stem Cell Reports 2016 2:236-247. 18. Zirra A, Wiethoff S, Patani R. 'Neural conversion and patterning of human pluripotent stem cells: a developmental perspective'. Stem Cells International 2016 8291260. doi: 10.1155/2016/8291260. 19. Balendra R, Patani R. 'Quo vadis MND?'. World J Methodol. 2016 26;6(1):56-64. 20. Patani R. Generating Diverse Spinal Motor Neuron Subtypes from Human Pluripotent Stem Cells. Stem Cells International 2016 1036974. doi: 10.1155/2016/1036974. 21. Wiethoff S, Arber C, Li A, Wray S, Houlden H, Patani R. Using human induced pluripotent stem cells to model cerebellar disease: Hope and hype. J Neurogenet. 2015 Jun-Sep;29(2- 3):95-102. This work emphasises the importance of interdisciplinary and team science, integrating stem cell biology, developmental biology, neuropathology, bioinformatics and RNA biology.
Start Year 2018
 
Title VCP INHIBITORS AND USES THEREOF FOR TREATMENT 
Description The present invention relates to inhibitors of Valosin-containing protein (VCP or p97) inhibitors and the use thereof in the treatment or prevention of diseases such as amyotrophic lateral sclerosis (ALS). In particular the present invention provides VCP inhibitors for use in a method of treating or preventing ALS wherein the subject has been identified as not having a disease-causing genetic mutation in a VCP gene (non-VCP-associated ALS). The invention also relates to methods of identifying a patient as not having a disease-causing mutation in a VCP gene. 
IP Reference 2109830.6 
Protection Patent / Patent application
Year Protection Granted
Licensed No
Impact None yet
 
Description @PataniLab Twitter 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact We have over 1300 followers on Twitter and regularly tweet about updates from our lab
Year(s) Of Engagement Activity 2015,2016,2017,2018,2019,2020
URL https://twitter.com/PataniLab
 
Description Profile Piece by Lancet Neurology 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Lancet Neurology, 2020: 'Rickie Patani' In context; lifeline; volume 19, issue 1, p35, january 01, 2020. DOI: https://doi.org/10.1016/S1474-4422(19)30408-9
Year(s) Of Engagement Activity 2020
URL https://doi.org/10.1016/S1474-4422(19)30408-9
 
Description Profile piece by Nature Medicine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Nature Medicine, 2020: 'Human stem cell models of disease and the prognosis of academic medicine' by Patani R. 2020 Apr;26(4):449. doi: 10.1038/s41591-020-0814-7. https://doi.org/10.1038/s41591-020-0814-7
Year(s) Of Engagement Activity 2020
URL https://doi.org/10.1038/s41591-020-0814-7
 
Description Profile piece for a PhD student in my lab. Nature, 2021: 'Where I work Hannah Franklin' by David Payne 480; Nature; Vol 592, 15 April 2021. doi: https://doi.org/10.1038/d41586-021-00957-5 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Nature, 2021: 'Where I work Hannah Franklin' by David Payne 480; Nature; Vol 592, 15 April 2021. doi: https://doi.org/10.1038/d41586-021-00957-5
Year(s) Of Engagement Activity 2021
URL https://doi.org/10.1038/d41586-021-00957-5
 
Description Star Cells: Innovative public engagement about the role of astrocytes in neurodegeneration. Star Cells uses dance and film to inform and illustrate the science of how the body moves and reacts, the project conveys the impact of neuromuscular diseases in a powerful visual medium that raises awareness of these conditions. A socially distanced, virtual promenade performance that remains in situ throughout the pandemic. Inspired by the work in the Patani Lab (Francis Crick Institute) and the Hodson 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Star Cells: Innovative public engagement about the role of astrocytes in neurodegeneration. Star Cells uses dance and film to inform and illustrate the science of how the body moves and reacts, the project conveys the impact of neuromuscular diseases in a powerful visual medium that raises awareness of these conditions. A socially distanced, virtual promenade performance that remains in situ throughout the pandemic. Inspired by the work in the Patani Lab (Francis Crick Institute) and the Hodson-Tole Lab (Manchester Metropolitan University, MMU); https://starcells.uk/meet-the-team/
Year(s) Of Engagement Activity 2021
URL https://starcells.uk/meet-the-team/
 
Description The Financial Times piece on my group's research project, 2019 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact https://www.ft.com/content/caac6b22-ba9b-11e9-8a88-aa6628ac896c
Year(s) Of Engagement Activity 2019
URL https://www.ft.com/content/caac6b22-ba9b-11e9-8a88-aa6628ac896c