Daniel A. Solomon

Bio: Daniel A. Solomon is an academic researcher from King's College London. The author has contributed to research in topics: Trinucleotide repeat expansion & Amyotrophic lateral sclerosis. The author has an hindex of 3, co-authored 4 publications receiving 145 citations. Previous affiliations of Daniel A. Solomon include University of London.

Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioural phenotypes that characterize ALS and FTLD

Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that are characterized by cytoplasmic aggregates and nuclear clearance of TAR DNA-binding protein 43 (TDP-43). Studies in Drosophila, zebrafish and mouse demonstrate that the neuronal dysfunction of TDP-43 is causally related to disease formation. However, TDP-43 aggregates are also observed in glia and muscle cells, which are equally affected in ALS and FTLD; yet, it is unclear whether glia- or muscle-specific dysfunction of TDP-43 contributes to pathogenesis. Here, we show that similar to its human homologue, Drosophila TDP-43, Tar DNA-binding protein homologue (TBPH), is expressed in glia and muscle cells. Muscle-specific knockdown of TBPH causes age-related motor abnormalities, whereas muscle-specific gain of function leads to sarcoplasmic aggregates and nuclear TBPH depletion, which is accompanied by behavioural deficits and premature lethality. TBPH dysfunction in glia cells causes age-related motor deficits and premature lethality. In addition, both loss and gain of Drosophila TDP-43 alter mRNA expression levels of the glutamate transporters Excitatory amino acid transporter 1 (EAAT1) and EAAT2. Taken together, our results demonstrate that both loss and gain of TDP-43 function in muscle and glial cells can lead to cytological and behavioural phenotypes in Drosophila that also characterize ALS and FTLD and identify the glutamate transporters EAAT1/2 as potential direct targets of TDP-43 function. These findings suggest that together with neuronal pathology, glial- and muscle-specific TDP-43 dysfunction may directly contribute to the aetiology and progression of TDP-43-related ALS and FTLD.

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.

Altered Phase Separation and Cellular Impact in C9orf72-Linked ALS/FTD.

Abstract: Since the discovery of the C9orf72 repeat expansion mutation as causative for chromosome 9-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in 2011, a multitude of cellular pathways have been implicated. However, evidence has also been accumulating for a key mechanism of cellular compartmentalization-phase separation. Liquid-liquid phase separation (LLPS) is fundamental for the formation of membraneless organelles including stress granules, the nucleolus, Cajal bodies, nuclear speckles and the central channel of the nuclear pore. Evidence has now accumulated showing that the formation and function of these membraneless organelles is impaired by both the toxic arginine rich dipeptide repeat proteins (DPRs), translated from the C9orf72 repeat RNA transcript, and the repeat RNA itself. Both the arginine rich DPRs and repeat RNA themselves undergo phase separation and disrupt the physiological phase separation of proteins involved in the formation of these liquid-like organelles. Hence abnormal phase separation may explain a number of pathological cellular phenomena associated with C9orf72-ALS/FTD. In this review article, we will discuss the principles of phase separation, phase separation of the DPRs and repeat RNA themselves and how they perturb LLPS associated with membraneless organelles and the functional consequences of this. We will then discuss how phase separation may impact the major pathological feature of C9orf72-ALS/FTD, TDP-43 proteinopathy, and how LLPS may be targeted therapeutically in disease.

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.

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.

TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle

Abstract: A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP-the gene that encodes TDP-43-that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here we show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.