Despite identification of more than twenty ALS-associated genes (at least half of which also cause the second most frequent dementia, frontotemporal dementia or FTD), the disease mechanism(s) are unknown. Exploiting transgenic and gene targeted mice we have constructed, as well as cell culture models, which we have established with prior support from this grant application, we now propose a multi PI effort comprised of three interrelated directions, each designed to uncover disease mechanism(s) underlying inherited and sporadic ALS/FTD. First, in light of emerging genetic evidence for incomplete disease penetrance from single mutations in C9orf72 and TDP-43 and identification of two or more ALS/FTD-linked gene mutations in multiple sporadic ALS or FTD patients, we will test the hypothesis of oligogenic mutant gene synergy as a cause/contributor of apparently sporadic ALS or FTD through use of multiple mouse lines each of which develops only partial ALS- or FTD-like disease. Similarly, recognizing that heterozygous missense or truncation mutants of Tank-binding kinase 1 (TBK1) have been identified as causative of ALS/FTD, we will use our newly generated mouse models to determine how TBK1 contributes to motor neuron health and the consequences of reduction of its activity, including determination of whether reduction in TBK1 synergizes with other ALS-linked mutations to exacerbate motor neuron or cognitive disease in existing mouse lines that develop only partial ALS- or FTD-like disease from TDP-43 or C9orf72 transgenes alone. Finally, the discoveries of 1) liquid-liquid de-mixing as a mechanism for intracellular compartmentalization and 2) that such repetitive phase separation can nucleate protein misfolding are seminal findings of extraordinary biological interest and ones that have profound implications for neurodegenerative diseases. Recognizing this, we will exploit three cell culture models that we have established in which de-mixing can be induced to identify determinants, including the role of TBK1, of intracellular TDP-43 liquid-liquid de-mixing and aggregation, and to determine if there is cell-to-cell transmission of aggregated TDP-43 and if so initiate tests of the mechanism(s) of intercellular transmission.

Public Health Relevance

Beginning with the recognition mutations in a common set of genes are causes of both the fatal motor neuron disease Amyotrophic Lateral Sclerosis (ALS) and the second most frequent dementia (frontotemporal dementia ? FTD), this effort seeks to uncover how mutation in these genes triggers either disease. Key questions to be tackled will be determining how mutation in more than one gene drives either disease, how partial inactivation of one specific gene results in ALS/FTD, and whether (and if so, how) there is disease- causing damage that spreads from cell to cell.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Gubitz, Amelie
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Ludwig Institute for Cancer Research Ltd
La Jolla
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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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