Jonah Dearlove

Bio: Jonah Dearlove is an academic researcher from King's College London. The author has contributed to research in topics: Vertebrate & Trinucleotide repeat expansion. The author has an hindex of 4, co-authored 4 publications receiving 87 citations. Previous affiliations of Jonah Dearlove include University of London.

A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-α mediates C9orf72-related neurodegeneration.

Abstract: Accumulation and aggregation of TDP-43 is a major pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 inclusions also characterize patients with GGGGCC (G4C2) hexanucleotide repeat expansion in C9orf72 that causes the most common genetic form of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Functional studies in cell and animal models have identified pathogenic mechanisms including repeat-induced RNA toxicity and accumulation of G4C2-derived dipeptide-repeat proteins. The role of TDP-43 dysfunction in C9ALS/FTD, however, remains elusive. We found G4C2-derived dipeptide-repeat protein but not G4C2-RNA accumulation caused TDP-43 proteinopathy that triggered onset and progression of disease in Drosophila models of C9ALS/FTD. Timing and extent of TDP-43 dysfunction was dependent on levels and identity of dipeptide-repeat proteins produced, with poly-GR causing early and poly-GA/poly-GP causing late onset of disease. Accumulating cytosolic, but not insoluble aggregated TDP-43 caused karyopherin-α2/4 (KPNA2/4) pathology, increased levels of dipeptide-repeat proteins and enhanced G4C2-related toxicity. Comparable KPNA4 pathology was observed in both sporadic frontotemporal dementia and C9ALS/FTD patient brains characterized by its nuclear depletion and cytosolic accumulation, irrespective of TDP-43 or dipeptide-repeat protein aggregates. These findings identify a vicious feedback cycle for dipeptide-repeat protein-mediated TDP-43 and subsequent KPNA pathology, which becomes self-sufficient of the initiating trigger and causes C9-related neurodegeneration.

Ancestral regulatory mechanisms specify conserved midbrain circuitry in arthropods and vertebrates.

Abstract: Corresponding attributes of neural development and function suggest arthropod and vertebrate brains may have an evolutionarily conserved organization. However, the underlying mechanisms have remained elusive. Here, we identify a gene regulatory and character identity network defining the deutocerebral–tritocerebral boundary (DTB) in Drosophila. This network comprises genes homologous to those directing midbrain-hindbrain boundary (MHB) formation in vertebrates and their closest chordate relatives. Genetic tracing reveals that the embryonic DTB gives rise to adult midbrain circuits that in flies control auditory and vestibular information processing and motor coordination, as do MHB-derived circuits in vertebrates. DTB-specific gene expression and function are directed by cis-regulatory elements of developmental control genes that include homologs of mammalian Zinc finger of the cerebellum and Purkinje cell protein 4. Drosophila DTB-specific cis-regulatory elements correspond to regulatory sequences of human ENGRAILED-2, PAX-2, and DACHSHUND-1 that direct MHB-specific expression in the embryonic mouse brain. We show that cis-regulatory elements and the gene networks they regulate direct the formation and function of midbrain circuits for balance and motor coordination in insects and mammals. Regulatory mechanisms mediating the genetic specification of cephalic neural circuits in arthropods correspond to those in chordates, thereby implying their origin before the divergence of deuterostomes and ecdysozoans.

A lineage-related reciprocal inhibition circuitry for sensory-motor action selection

Abstract: The insect central complex and vertebrate basal ganglia are forebrain centres involved in selection and maintenance of behavioural actions. However, little is known about the formation of the underlying circuits, or how they integrate sensory information for motor actions. Here, we show that paired embryonic neuroblasts generate central complex ring neurons that mediate sensory-motor transformation and action selection in Drosophila. Lineage analysis resolves four ring neuron subtypes, R1-R4, that form GABAergic inhibition circuitry among inhibitory sister cells. Genetic manipulations, together with functional imaging, demonstrate subtype-specific R neurons mediate the selection and maintenance of behavioural activity. A computational model substantiates genetic and behavioural observations suggesting that R neuron circuitry functions as salience detector using competitive inhibition to amplify, maintain or switch between activity states. The resultant gating mechanism translates facilitation, inhibition and disinhibition of behavioural activity as R neuron functions into selection of motor actions and their organisation into action sequences.

Ancestral Regulatory Mechanisms Specify Conserved Midbrain Circuitry in Arthropods and Vertebrates

Abstract: Corresponding attributes of neural development and function suggest arthropod and vertebrate brains may have an evolutionarily conserved organization. However, the underlying mechanisms have remained elusive. Here we identify a gene regulatory and character identity network defining the deutocerebral-tritocerebral boundary (DTB) in Drosophila. We show this network comprises genes homologous to those directing midbrain-hindbrain boundary (MHB) formation in vertebrates and their closest chordate relatives. Genetic tracing reveals that the embryonic DTB gives rise to adult midbrain circuits that in flies control auditory and vestibular information processing and motor coordination, as do MHB-derived circuits in vertebrates. DTB-specific gene expression and function is directed by cis-regulatory elements (CREs) of developmental control genes that include homologs of mammalian Zinc finger of the cerebellum and Purkinje cell protein 4. Moreover, Drosophila DTB-specific CREs correspond to regulatory sequences of human ENGRAILED-2, PAX-2 and DACHSHUND-1 that direct MHB-specific expression in the embryonic mouse brain. Together, these findings imply ancestral regulatory mechanisms mediating the genetic specification of midbrain-cerebellar circuitry for balance and motor control that may predated the radiation of cephalic nervous systems across the animal kingdom.

Is this a practical approach

Abstract: 1. Health care is a human right. 2. The care of the individual is at the center of health care, but the whole system needs to work to improve the health of populations. 3. The health care system must treat illness, alleviate suffering and disability, and promote health. 4. Cooperation with each other, those served, and those in other sectors is essential for all who work in health care. 5. All who provide health care must work to improve it. 6. Do no harm.

C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD (P4.001)

Abstract: OBJECTIVE: To report a novel transgenic mouse model of ALS/FTD from hexanucleotide expansion mutations in the C9orf72 gene. BACKGROUND: Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the first intron of the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. DESIGN/METHODS: We generated transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (~100-1000 repeats; C9-BACexp). Mice were analyzed pathologically and behaviorally, and cortical cells were cultured. RESULTS: C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat associated non-ATG (RAN) translated dipeptides. RAN dipeptides and RNA foci were generated at levels similar to those observed in patient tissues, and could be suppressed by antisense oligonucleotides targeting human C9orf72 in cortical cultures from the mice. Nucleolin distribution was altered supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. CONCLUSIONS: Despite early and widespread production of RNA foci and RAN dipeptide inclusions in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptide production occur presymptomatically in humans and may not be sufficient to drive cell death in the absence of overexpression or other stressors. Disclosure: Dr. Baloh has nothing to disclose. Dr. O9Rourke has nothing to disclose. Dr. Bell has nothing to disclose. Dr. Bogdonik has nothing to disclose. Dr. Muhammad has nothing to disclose. Dr. Gendron has nothing to disclose. Dr. Kim has nothing to disclose. Dr. Austin has nothing to disclose. Dr. Cady has nothing to disclose. Dr. Liu has nothing to disclose. Dr. Zarrow has nothing to disclose. Dr. Grant has nothing to disclose. Dr. Ho has nothing to disclose. Dr. Carmona has nothing to disclose. Dr. Simpkinson has nothing to disclose. Dr. Wu has nothing to disclose. Dr. Daughrity has nothing to disclose. Dr. Dickson has nothing to disclose. Dr. Harms has received personal compensation for activities as an expert witness testimony. Dr. Harms has received research support from Merck, Isis Pharmaceuticals, and Biogen Idec. Dr. Petrucelli has nothing to disclose. Dr. Lutz has nothing to disclose.

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Abstract: Since its discovery as a primary component in cytoplasmic aggregates in post-mortem tissue of patients with Amyotrophic Lateral Sclerosis (ALS), TAR DNA Binding Protein 43 kDa (TDP-43) has remained a central focus to understand the disease. TDP-43 links both familial and sporadic forms of ALS as mutations are causative for disease and cytoplasmic aggregates are a hallmark of nearly all cases, regardless of TDP-43 mutational status. Research has focused on the formation and consequences of cytosolic protein aggregates as drivers of ALS pathology through both gain- and loss-of-function mechanisms. Not only does aggregation sequester the normal function of TDP-43, but these aggregates also actively block normal cellular processes inevitably leading to cellular demise in a short time span. Although there may be some benefit to therapeutically targeting TDP-43 aggregation, this step may be too late in disease development to have substantial therapeutic benefit. However, TDP-43 pathology appears to be tightly linked with its mislocalization from the nucleus to the cytoplasm, making it difficult to decouple the consequences of nuclear-to-cytoplasmic mislocalization from protein aggregation. Studies focusing on the effects of TDP-43 mislocalization have demonstrated both gain- and loss-of-function consequences including altered splicing regulation, over responsiveness to cellular stressors, increases in DNA damage, and transcriptome-wide changes. Additionally, mutations in TARDBP confer a baseline increase in cytoplasmic TDP-43 thus suggesting that small changes in the subcellular localization of TDP-43 could in fact drive early pathology. In this review, we bring forth the theme of protein mislocalization as a key mechanism underlying ALS, by highlighting the importance of maintaining subcellular proteostasis along with the gain- and loss-of-functional consequences when TDP-43 localization is dysregulated. Additional research, focusing on early events in TDP-43 pathogenesis (i.e. to the protein mislocalization stage) will provide insight into disease mechanisms, therapeutic targets, and novel biomarkers for ALS.

Ring Attractor Dynamics Emerge from a Spiking Model of the Entire Protocerebral Bridge.

Abstract: Animal navigation is accomplished by a combination of landmark-following and dead reckoning based on estimates of self motion. Both of these approaches require the encoding of heading information, which can be represented as an allocentric or egocentric azimuthal angle. Recently, Ca2+ correlates of landmark position and heading direction, in egocentric coordinates, were observed in the ellipsoid body (EB), a ring-shaped processing unit in the fly central complex (Seelig and Jayaraman, 2015). These correlates displayed key dynamics of so-called ring attractors, namely: 1) responsiveness to the position of external stimuli, 2) persistence in the absence of external stimuli, 3) locking onto a single external stimulus when presented with two competitors, 4) stochastically switching between competitors with low probability, and 5) sliding or jumping between positions when an external stimulus moves. We hypothesized that ring attractor-like activity in the EB arises from reciprocal neuronal connections to a related structure, the protocerebral bridge (PB). Using recent light-microscopy resolution catalogues of neuronal cell types in the PB (Wolff et al., 2015; Lin et al., 2013), we determined a connectivity matrix for the PB-EB circuit. When activity in this network was simulated using a leaky-integrate-and-fire model, we observed patterns of activity that closely resemble the reported Ca2+ phenomena. All qualitative ring attractor behaviors were recapitulated in our model, allowing us to predict failure modes of the putative PB-EB ring attractor and the circuit dynamics phenotypes of thermogenetic or optogenetic manipulations. Ring attractor dynamics emerged under a wide variety of parameter configurations, even including non-spiking leaky-integrator implementations. This suggests that the ring-attractor computation is a robust output of this circuit, apparently arising from its high-level network properties (topological configuration, local excitation and long-range inhibition) rather than fine-scale biological detail.

Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation.

Abstract: Cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP43; also known as TARDBP or TDP-43) is a key pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP43 typically resides in the nucleus but can shuttle between the nucleus and the cytoplasm to exert its multiple functions, which include regulation of the splicing, trafficking and stabilization of RNA. Cytoplasmic mislocalization and nuclear loss of TDP43 have both been associated with ALS and FTD, suggesting that calibrated levels and correct localization of TDP43 — achieved through an autoregulatory loop and tightly controlled nucleocytoplasmic transport — safeguard its normal function. Furthermore, TDP43 can undergo phase transitions, including its dispersion into liquid droplets and its accumulation into irreversible cytoplasmic aggregates. Thus, autoregulation, nucleocytoplasmic transport and phase transition are all part of an intrinsic control system regulating the physiological levels and localization of TDP43, and together are essential for the cellular homeostasis that is affected in neurodegenerative disease. Accumulation of TAR DNA-binding protein 43 (TDP43) in the neuronal cytoplasm and its loss from the nucleus are characteristic features of several neurodegenerative diseases. Tziortzouda, Van Den Bosch and Hirth describe three intrinsic mechanisms that control TDP43 levels and localization and are altered to drive pathology.