Motor and sensory neurons of the periphery are among the largest cells, with volumes up to 5,000 times that typical for animal cells. Most of this volume is acquired just after stable synapse formation and concomitant with myelination, during which time the axons grow in diameter by more than an order of magnitude. One basic cell biological question is how is this volume expansion, a key component for conduction velocity, is mediated. Earlier efforts using classical and molecular genetics have demonstrated that incorporation into axons of an ordered array of neurofilaments is essential for radial growth. Using gene targeting and gene replacement, the principles through which neurofilaments structure axoplasm to support axonal volume will be determined. This will include a focus on identification of the interfilament crosslinkers that probably support growth through formation a deformable, three dimensional, space filling, structural array. Beyond this, multiple preceding lines of evidence, including use of transgenic mice expressing mutated neurofilament genes, has demonstrated that disorganization/damage to neurofilaments can itself provoke death of motor neurons that mimics most aspects of the most abundant human adult motor neuron disease, amyotrophic lateral sclerosis (ALS). With neurofilamentous pathology frequently reported in human ALS, a search will be undertaken for possible neurofilament mutations or variants as causes or contributors to human ALS. A parallel approach will search for covalent damage to neurofilaments and their associated components that may develop during ALS. A high through put screen will be conducted for agents that can provoke disassembly of neurofilaments. Lastly, for human ALS, a proportion of dominantly inherited disease arises from mutation in superoxide dismutase (SOD 1), but the mechanism through which mutation in this ubiquitously expressed protein provokes late onset, selective motor neuron killing has remained elusive. To this, transgenic mice that develop disease from expressing any of three SOD 1 mutants, as well as cell cultures from those mice, will be used to test how toxicity of the mutants is related to binding of the catalytic copper or zinc, whether toxicity is cell autonomous (that is, arises uniquely from damage directly within motor neurons) and how aggregation of mutant SOD 1, and compromise in protein folding and catabolism, contributes to toxicity.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Refolo, Lorenzo
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ludwig Institute for Cancer Research
La Jolla
United States
Zip Code
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

Showing the most recent 10 out of 71 publications