Rickie Patani

Rickie Patani
University College London | UCL · Institute of Neurology

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163
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Publications

Publications (163)
Article
Axonal Pathways This cover depicts artistic adaptations of timelapse imaging of human motor axons growing on the bioengineered arrays described in article number 2101817 by Andrea Serio and co‐workers, colorcoded to show how the axon elongation proceeds asynchronously over time.
Article
Full-text available
Accumulating evidence suggests that neurodegenerative diseases are not merely neuronal in nature but comprise multicellular involvement, with astrocytes emerging as key players. The pathomechanisms of several neurodegenerative diseases involve the deposition of misfolded protein aggregates in neurons that have characteristic prion-like behaviours s...
Article
Stem cell‐based experimental platforms for neuroscience can effectively model key mechanistic aspects of human development and disease. However, conventional culture systems often overlook the engineering constraints that cells face in vivo. This is particularly relevant for neurons covering long range connections such as spinal motor neurons (MNs)...
Article
Amyotrophic lateral sclerosis is a rapidly progressive and fatal disease. Although astrocytes are increasingly recognized contributors to the underlying pathogenesis, the cellular autonomy and uniformity of astrocyte reactive transformation in different genetic forms of amyotrophic lateral sclerosis remain unresolved. Here we systematically examine...
Article
Astrocytes contribute to motor neuron death in amyotrophic lateral sclerosis (ALS), but whether they adopt deleterious features consistent with inflammatory reactive states remains incompletely resolved. To identify inflammatory reactive features in ALS human induced pluripotent stem cell (hiPSC)–derived astrocytes, we examined transcriptomics, pro...
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The microtubule-associated protein tau gene (MAPT) 10+16 intronic mutation causes frontotemporal lobar degeneration (FTLD) by increasing expression of four-repeat (4R)-tau isoforms. We investigated the potential role for astrocytes in the pathogenesis of FTLD by studying the expression of 4R-tau. We derived astrocytes and neurons from induced pluri...
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Full-text available
Objectives Although morphological attributes of cells and their substructures are recognized readouts of physiological or pathophysiological states, these have been relatively understudied in amyotrophic lateral sclerosis (ALS) research. Materials and Methods In this study, we integrate multichannel fluorescence high-content microscopy data with d...
Preprint
Full-text available
Stem cell-based experimental platforms for neuroscience can effectively model key mechanistic aspects of human development and disease. However, conventional culture systems often overlook the engineering constraints that cells face in vivo. This is particularly relevant for neurons covering long range connections such as spinal motor neurons (MNs)...
Article
Full-text available
Mutations causing amyotrophic lateral sclerosis (ALS) often affect the condensation properties of RNA-binding proteins (RBPs). However, the role of RBP condensation in the specificity and function of protein-RNA complexes remains unclear. We created a series of TDP-43 C-terminal domain (CTD) variants that exhibited a gradient of low to high condens...
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RNA binding proteins have been shown to play a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Mutations in valosin-containing protein (VCP/p97) cause ALS and exhibit the hallmark nuclear-to-cytoplasmic mislocalization of RNA binding proteins (RBPs). However, the mechanism by which mutations in VCP lead to this mislocalization...
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The human genome expresses thousands of natural antisense transcripts (NAT) that can regulate epigenetic state, transcription, RNA stability or translation of their overlapping genes1,2. Here we describe MAPT-AS1, a brain-enriched NAT that is conserved in primates and contains an embedded mammalian-wide interspersed repeat (MIR), which represses ta...
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Neurodegenerative diseases are a group of largely incurable disorders characterised by the progressive loss of neurons and for which often the molecular mechanisms are poorly understood. To bridge this gap, researchers employ a range of techniques. A very prominent and useful technique adopted across many different fields is imaging and the analysi...
Preprint
Full-text available
Although morphological attributes of cells and their substructures are recognized readouts of physiological or pathophysiological states, these have been relatively understudied in amyotrophic lateral sclerosis (ALS) research. In this study we integrate multichannel fluorescence high-content microscopy data with deep-learning imaging methods to rev...
Article
Full-text available
RNA binding proteins fulfil a wide number of roles in gene expression. Multiple mechanisms of RNA binding protein dysregulation have been implicated in the pathomechanisms of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Oxidative stress and mitochondrial dysfunction also play important roles in these diseases. I...
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Several studies have shown that human induced pluripotent stem cell (iPSC)-derivatives are essentially fetal in terms of their maturational status. Inducing ageing in iPSC-motor neuron (MN) models of amyotrophic lateral sclerosis (ALS) has the potential to capture pathology with higher fidelity and consequently improve translational success. We sho...
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We recently described aberrantly increased cytoplasmic SFPQ intron-retaining transcripts (IRTs) and concurrent SFPQ protein mislocalization as new hallmarks of amyotrophic lateral sclerosis (ALS). However the generalizability and potential roles of cytoplasmic IRTs in health and disease remain unclear. Here, using time-resolved deep-sequencing of n...
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Full-text available
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 wit...
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Full-text available
Histopathological analysis of tissue sections is invaluable in neurodegeneration research. However, cell-to-cell variation in both the presence and severity of a given phenotype is a key limitation of this approach, reducing the signal to noise ratio and leaving unresolved the potential of single-cell scoring for a given disease attribute. Here, we...
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Full-text available
A number of age-associated neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS), possess a shared characteristic of region-specific neurodegeneration. However, the mechanisms which determine why particular regions within the nervous system are selectively vulnerable to neur...
Preprint
Full-text available
Intron retention (IR) is now recognized as a dominant splicing event during motor neuron (MN) development, however the role and regulation of intron-retaining transcripts (IRTs) localized to the cytoplasm remain particularly understudied. By resolving the spatiotemporal dynamics of IR underlying distinct stages of MN lineage restriction, we identif...
Preprint
Full-text available
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now widely considered to be part of a disease spectrum with the identification of common pathological features and genetic causes. However, despite these advances, there remains no effective therapy for these conditions. In this study we demonstrate that mice expressing mutan...
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Full-text available
Microglia are the primary immune cells of the CNS, carrying out key homeostatic roles and undergoing context-dependent and temporally regulated changes in response to injury and neurodegenerative diseases. Microglia have been implicated in playing a role in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by extensive...
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Full-text available
Both astrocytes and microglia fulfil homeostatic and immune functions in the healthy CNS. Dysfunction of these cell types have been implicated in the pathomechanisms of several neurodegenerative diseases. Understanding the cellular autonomy and early pathological changes in these cell types may inform drug screening and compound development. While...
Preprint
Full-text available
The MAPT 10+16 intronic mutation causes frontotemporal lobar degeneration (FTLD) by increasing expression of four-repeat (4R)-tau isoforms. We investigated the potential role for astrocytes in the pathogenesis of FTLD by studying the expression of 4R-tau. We derived astrocytes and neurons from induced pluripotent stem cells from two asymptomatic 10...
Article
Full-text available
Novel functional coding sequences (altORFs) are camouflaged within annotated ones (CDS) in a different reading frame. We show here that an altORF is nested in the FUS CDS, encoding a conserved 170 amino acid protein, altFUS. AltFUS is endogenously expressed in human tissues, notably in the motor cortex and motor neurons. Over-expression of wild-typ...
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Full-text available
RNA-binding proteins (RBPs) have been shown to play a key role in the pathogenesis of a variety of neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is an exemplar neurodegenerative disease characterised by rapid progression and relatively selective motor neuron loss. Nuclear-to-cytoplasmic mislocalisation and accumulation of RBPs ha...
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Traumatic brain injury leads to cellular damage which in turn results in the rapid release of damage-associated molecular patterns (DAMPs) that prompt resident cells to release cytokines and chemokines. These in turn rapidly recruit neutrophils, which assist in limiting the spread of injury and removing cellular debris. Microglia continuously surve...
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The majority of neuroscience research has focused on nerve cells called neurons. But there are just as many star-shaped cells called astrocytes in the brain. In this article, we discuss how astrocytes have many really important roles for keeping neurons healthy. We also describe how scientists are using stem cell technology to study human astrocyte...
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Gene expression studies suggest that aging of the human brain is determined by a complex interplay of molecular events, although both its region-and cell-type specific consequences remain poorly understood. Here, we extensively characterized aging-altered gene expression changes across 10 human brain regions from 480 individuals ranging in age from...
Preprint
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The development of human induced pluripotent stem cells (hiPSC) has greatly aided our ability to model neurodegenerative diseases. However, generation of midbrain dopaminergic (mDA) neurons is a major challenge and protocols are variable. Here, we developed a method to differentiate hiPSCs into enriched populations (>80%) of mDA neurons using only...
Preprint
Full-text available
Histopathological analysis of tissue sections is an invaluable resource in neurodegeneration research. Importantly, cell-to-cell variation in both the presence and severity of a given phenotype is however a key limitation of this approach, reducing the signal to noise ratio and leaving unresolved the potential of single-cell scoring for a given dis...
Article
Introduction Amyotrophic lateral sclerosis (ALS) is a devastating disease with a lifetime risk of approximately 1:400. It is incurable and invariably fatal. Average survival is between 3 and 5 years and patients become increasingly paralyzed, losing the ability to speak, eat, and breathe. Therapies in development either (i) target specific familial...
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This scientific commentary refers to ‘Aberrant interaction between FUS and SFPQ in neurons of a wide range of FTLD spectrum diseases’, by Ishigaki etal. (doi:10.1093/brain/awaa196).
Preprint
Full-text available
We recently described aberrant cytoplasmic SFPQ intron-retaining transcripts (IRTs) and concurrent SFPQ protein mislocalization as a new hallmark of amyotrophic lateral sclerosis (ALS). However the generalizability and potential roles of cytoplasmic IRTs in health and disease remain unclear. Here, using time-resolved deep-sequencing of nuclear and...
Preprint
Full-text available
RNA-binding proteins (RBPs) play diverse roles in regulating co-transcriptional RNA-processing and chromatin functions, but our knowledge of the repertoire of chromatin-associated RBPs (caRBPs) and their interactions with chromatin remains limited. Here, we developed SPACE (Silica Particle Assisted Chromatin Enrichment) to isolate global and region...
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Full-text available
Increasing evidence has suggested that astrocytes demonstrate striking regionally allocated functional heterogeneity. Here, we discuss how this spatiotemporally encoded diversity determines the astrocytic phenotype along a finely grained spectrum from neuroprotective to deleterious states. With increasing recognition of their diverse and evolving r...
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Full-text available
Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by motor neuron loss, resulting in muscle wasting, paralysis and eventual death. A key pathological feature of ALS is cytoplasmically mislocalized and aggregated TDP-43 protein in >95% of cases, which is considered to have prion-like properties. Historical...
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Full-text available
With an ageing population comes an inevitable increase in the prevalence of age-associated neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), a relentlessly progressive and universally fatal disease characterized by the degeneration of upper and lower motor neurons within the brain and spinal cord. Indeed, the physiological pr...
Preprint
Full-text available
Novel functional coding sequences (altORFs) are camouflaged within annotated ones (CDS) in a different reading frame. We discovered an altORF nested in the FUS CDS encoding a conserved protein, altFUS. We thus demonstrate the dual-coding nature of the Amyotrophic Lateral Sclerosis (ALS)-associated FUS gene. AltFUS is endogenously expressed in human...
Article
Neuroinflammation has been shown to mediate the pathophysiological response following traumatic brain injury (TBI). Accumulating evidence implicates astrocytes as key immune cells within the central nervous system (CNS), displaying both pro- and anti-inflammatory properties. The aim of this study was to investigate how in vitro human astrocyte cult...
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Full-text available
Mutations causing amyotrophic lateral sclerosis (ALS) clearly implicate ubiquitously expressed and predominantly nuclear RNA binding proteins, which form pathological cytoplasmic inclusions in this context. However, the possibility that wild-type RNA binding proteins mislocalize without necessarily becoming constituents of cytoplasmic inclusions th...
Preprint
Full-text available
Rare amyotrophic lateral sclerosis (ALS)-causing mutations clearly implicate ubiquitously expressed and predominantly nuclear RNA binding proteins (RBPs), which form pathological cytoplasmic inclusions in this context. However, it remains possible that RBPs can mislocalize without necessarily becoming constituents of cytoplasmic ALS inclusions. We...
Article
Full-text available
Spinal and bulbar muscular atrophy (SBMA) results from a CAG repeat expansion within the androgen receptor gene (AR). It is unclear why motor neurons selectively degenerate and there are currently no treatments for this debilitating disease. To uncover the causative genes and pathways involved in motor neuron dysfunction, we undertook transcriptomi...
Article
Objectives The objective of this study was to investigate how in vitro astrocyte cultures respond to cytokine pro- and anti-inflammatory cytokine concentrations, corresponding to those seen in the aftermath of human TBI, by analysing downstream cytokine generation. Design In vitro study. Subjects Human induced pluripotent stem cells (iPSC)-derive...
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Full-text available
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative condition that is invariably fatal, usually within 3 to 5 years of diagnosis. The etiology of ALS remains unresolved and no effective treatments exist. There is therefore a desperate and unmet need for discovery of disease mechanisms to guide novel therapeutic strat...
Article
Full-text available
Mutations causing amyotrophic lateral sclerosis (ALS) strongly implicate ubiquitously expressed regulators of RNA processing. To understand the molecular impact of ALS-causing mutations on neuronal development and disease, we analysed transcriptomes during in vitro differentiation of motor neurons (MNs) from human control and patient-specific VCP m...
Data
3D projections were generated from confocal stacks through the assemblies. Scale bar, 4 μm.
Data
3D volume through a bright assembly in a HEK293 cell. The assembly is made up of a dense meshwork of fibers. The assembly is not membrane bound and it generally excludes ribosomes. Double membrane (right) is the nuclear envelope.
Data
Time-lapse TIRF microscopy shows the conversion of 25QP-GFP droplets to solid-like structures. Note the growth of spikes from the edges of the droplets and the depletion of the liquid-like component at the centers of droplets.
Data
Time-lapse TIRF microscopy of hexanediol addition to 25QP-GFP droplets. The hexanediol moves across the field of view, dissolving the liquid-like component of the droplets and leaving behind elongated structures that are likely early solid-like features.
Data
Time-lapse fluorescence microscopy shows the formation of a dim assembly that remains intact during division of a HEK293 cell. The dim assembly then converts to a bright assembly, which rapidly sequesters the cytoplasmic fluorescence in the affected cell.
Data
Hexanediol was added to a yeast cell, causing the dim assemblies to dissolve. When hexanediol was washed away, the assemblies rapidly reformed. Time-lapse fluorescence microscopy (5 s frame rate) was used to record the movie.
Data
Recombinant 25QP-GFP was exposed to 10% dextran to induce droplet formation. TIRF microscopy shows droplets fusing and relaxing back into a spherical shape.
Article
Parkinson's disease (PD) is a common neurodegenerative disease characterised initially loss of dopaminergic neurons in the substantia nigra (SN) and later widespread nondopaminergic neuronal loss including in the cortex. Genetic mutations can cause familial PD, but the sequence of molecular events that trigger neuronal vulnerability is poorly under...
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Full-text available
Huntington’s disease is caused by an abnormally long po lyglutamine tract in the huntingtin protein. This leads to the generation and deposition of N - terminal exon1 fragments of the protein in intracellular aggregates . We combine d electro n tomography and quantitative fluorescence microscopy to analyse the structural and materia l properties of...
Article
become specialized to optimize circuit performance remains unclear. Large fast α- motor neurons (FαMNs) of spinal cord innervate fast-twitch muscles that generate peak strength. We report that ventral horn astrocytes express the inward rectifying potassium channel Kir4.1 (aka, KCNJ10) around MNs in a VGLUT1-dependent manner. Loss-of astrocyte-encod...
Data
3D reconstruction of nuclear morphology (LAMIN A/C in green) in a human artificial muscle derived from healthy donor hiPSC (WT control).
Data
Video S2. Nuclear Morphology in LMNA Mutant Artificial Muscles, Related to Figure 3 3D reconstruction of nuclear morphology (LAMIN A/C in green) in a human artificial muscle derived from LMNA-mutant hiPSC. Note the presence of elongated and deformed nuclei.