This application is aimed at elucidating the fundamental role of neurofilament subunits (NF-L, NF-M, NF-H) in specifying the axonal volume of neural cells and their role in motor neuron disease.
Aim 1 will continue the investigation of the mechanism of neurofilament dependent growth using transgenic mice that over express or are deleted for each subunit. In particular the role played by the phosphorylated tail domains of NF-M and NF-H in specifying the three dimensional array of neurofilaments and how they are linked to other axonal components will be examined.
Aim 2 will study the mechanism of neurofilament- dependent motor neuron disease, expanding previous observations that increased neurofilament burden in axons or expression of a mutant NF-L subunit cause selective motor neuron failure in transgenic mice. Point mutations in superoxide dismutase 1 (SOD1) which cause amyotrophic lateral sclerosis (ALS) in human also cause motor neuron disease in transgenic mice and Aim 3 will investigate the mechanism by which defects in this ubiquitously expressed cytoplasmic protein lead to the selective death of motor neurons. Experiments will test directly whether the toxic properties of SOD1 mutations arise through an effect on neurofilament accumulation and transport.
| McMahon, Moira A; Prakash, Thazha P; Cleveland, Don W et al. (2018) Chemically Modified Cpf1-CRISPR RNAs Mediate Efficient Genome Editing in Mammalian Cells. Mol Ther 26:1228-1240 |
| Gao, Fen-Biao; Richter, Joel D; Cleveland, Don W (2017) Rethinking Unconventional Translation in Neurodegeneration. Cell 171:994-1000 |
| Ditsworth, Dara; Maldonado, Marcus; McAlonis-Downes, Melissa et al. (2017) Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis. Acta Neuropathol 133:907-922 |
| Da Cruz, Sandrine; Bui, Anh; Saberi, Shahram et al. (2017) Misfolded SOD1 is not a primary component of sporadic ALS. Acta Neuropathol 134:97-111 |
| Taylor, J Paul; Brown Jr, Robert H; Cleveland, Don W (2016) Decoding ALS: from genes to mechanism. Nature 539:197-206 |
| Quaegebeur, Annelies; Segura, Inmaculada; Schmieder, Roberta et al. (2016) Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism. Cell Metab 23:280-91 |
| Da Cruz, Sandrine; Cleveland, Don W (2016) CELL BIOLOGY. Disrupted nuclear import-export in neurodegeneration. Science 351:125-6 |
| Sun, Shuying; Ling, Shuo-Chien; Qiu, Jinsong et al. (2015) ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. Nat Commun 6:6171 |
| Israelson, Adrian; Ditsworth, Dara; Sun, Shuying et al. (2015) Macrophage migration inhibitory factor as a chaperone inhibiting accumulation of misfolded SOD1. Neuron 86:218-32 |
| Bertuzzi, Stefano; Cleveland, Don W (2015) The curious incident of the translational dog that didn't bark. Trends Cell Biol 25:187-9 |
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