Knock-out and transgenic mouse models of tauopathies. by Denk, F, Wade-Martins, R

“…Here we review the range of Mapt knock-out and MAPT transgenic mouse models which have proven successful at providing insights into the molecular mechanisms of neurodegenerative disease. …”

Application of CRISPR/Cas9 editing and digital droplet PCR in human iPSCs to generate novel knock-in reporter lines to visualize dopaminergic neurons by Überbacher, C, Obergasteiger, J, Volta, M, Venezia, S, Müller, S, Pesce, I, Pizzi, S, Lamonaca, G, Picard, A, Cattelan, G, Pesce, I, Malpeli, G, Zoli, M, Beccano-Kelly, D, Flynn, R, Wade-Martins, R, Pramstaller, P, Hicks, A, Cowley, S, Corti, C

“…The knock-in cell lines that we created show a functioning fluorescent reporter system for DA neurons that are identifiable by flow cytometry.…”

Epigenetic modification of the frataxin gene for the treatment of Friedreich’s ataxia by Vilema Enriquez, MG

“…Using a human FXN-GAA-Luciferase (FXN-GAA-Luc) repeat expansion reporter model of FRDA, HDAC3 knock-down was shown to increase FXN mRNA levels with no effect on protein, while G9a knock-down did not show an effect on either FXN mRNA or protein levels. …”

Insights into LRRK2 function and dysfunction from transgenic and knockout rodent models. by Sloan, M, Alegre-Abarrategui, J, Wade-Martins, R

“…Numerous attempts have therefore been made to model PD in rodents via the transgenic expression of LRRK2 and its mutant variants and to elucidate the function of LRRK2 by knocking out rodent Lrrk2. Although these models often only partially recapitulate PD pathology, they have helped to elucidate both the normal and pathological function of LRRK2. …”

A novel method for autophagy detection in primary cells: impaired levels of macroautophagy in immunosenescent T cells. by Phadwal, K, Alegre-Abarrategui, J, Watson, A, Pike, L, Anbalagan, S, Hammond, E, Wade-Martins, R, McMichael, A, Klenerman, P, Simon, A

“…We validate this method on cell lines and primary cells knocked down for essential autophagy genes. Also, using this method we show that T cells have higher autophagic activity than B cells. …”

MAPT genetic variation and neuronal maturity alter isoform expression affecting axonal transport in iPSC-derived dopamine neurons. by Beevers, J, Lai, M, Collins, E, Booth, H, Zambon, F, Parkkinen, L, Vowles, J, Cowley, S, Wade-Martins, R, Caffrey, T

“…Mature dopaminergic neuronal cultures display haplotype differences in expression, with H1 expressing 22% higher levels of MAPT transcripts than H2 and H2 expressing 2-fold greater exon 3+ transcripts than H1. Furthermore, knocking down adult tau protein variants alters axonal transport velocities in mature iPSC-derived dopaminergic neuronal cultures. …”

Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation. by Shipton, O, Leitz, JR, Dworzak, J, Acton, C, Tunbridge, E, Denk, F, Dawson, H, Vitek, M, Wade-Martins, R, Paulsen, O, Vargas-Caballero, M

“…We used wild-type mice and mice with a genetic knock-out of tau protein and recorded field potentials in an acute slice preparation. …”

Familial Alzheimer's disease coding mutations reduce Presenilin-1 expression in a novel genomic locus reporter model. by Ahmadi, S, Wade-Martins, R

“…The PS1-WT-BAC construct restored γ-secretase function, whereas the mutant PS1 BACs demonstrated partial to complete loss of enzymatic activity when stably expressed in a PS double knock-out clonal cell line. We then engineered WT and mutant human PS1-BAC-Luciferase whole genomic locus reporter transgenes, which we transiently transduced in mouse and human non-neuronal and neuronal-like cells, respectively. …”

The effect of alpha-synuclein knockdown on MPP+ toxicity in models of human neurons. by Fountaine, T, Venda, L, Warrick, N, Christian, H, Brundin, P, Channon, K, Wade-Martins, R

“…Here we show that differentiated human dopaminergic neuron-like cells also have increased resistance to 1-methyl-4-phenylpyridine (MPP+), the active metabolite of MPTP, when alpha-synuclein is knocked down using RNA interference. In attempting to understand how this occurred we found that lowering alpha-synuclein levels caused changes to intracellular vesicles, dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2), each of which is known to be an important component of the early events leading to MPP+ toxicity. …”

A common variant associated with dyslexia reduces expression of the KIAA0319 gene. by Dennis, M, Paracchini, S, Scerri, T, Prokunina-Olsson, L, Knight, J, Wade-Martins, R, Coggill, P, Beck, S, Green, E, Monaco, A

“…Additionally, we found that the presence of this rs9461045 dyslexia-associated allele creates a nuclear protein-binding site, likely for the transcriptional silencer OCT-1. Knocking down OCT-1 expression in the neuronal cell line SHSY5Y using an siRNA restores KIAA0319 expression from the risk haplotype to nearly that seen from the non-risk haplotype. …”

Tau depletion in human neurons mitigates Aβ-driven toxicity by Ng, B, Vowles, J, Bertherat, F, Abey, A, Kilfeather, P, Beccano-Kelly, D, Stefana, MI, O’Brien, DP, Bengoa-Vergniory, N, Carling, PJ, Todd, JA, Caffrey, TM, Connor-Robson, N, Cowley, SA, Wade-Martins, R

“…Previous studies in mouse models with a targeted knock-out of the microtubule-associated protein tau (Mapt) gene demonstrated that Aβ-driven toxicity is tau-dependent. …”

Ca2+ cellular compartment-specific deficits in iPSC-derived neuronal models of Parkinson's disease by Caiazza, MC

“…Further investigation of the source of the deficit was pursued in a functional genetics experiment which employs CRISPRi knock-down of calcium channels and calcium regulators.…”