A proportion of dominantly inherited ALS arises from mutation in superoxide dismutase (SOD1). Accumulation of misfolded SOD1 is widely recognized as a component of this toxicity, especially its aggregation onto mitochondria within spinal cord. How mitochondrial composition is affected by mutant SOD1 will be determined using quantitative SILAM mass spectrometry. The mechanism(s) through which ALS-linked mutations aggregate and damage mitochondria only in affected tissues will be also be determined, focusing on our discovery of a chaperone that can block misfolded SOD1 accumulation in non-neuronal cells. Combining 1) Barres'discovery of a role for complement in synaptic pruning and 2) our discovery that components of the complement cascade are induced in motor neurons early in SOD1 mutant-mediated disease, gene disruption will now be used to test the role in disease pathogenesis of complement induction within motor neurons. We previously demonstrated that toxicity from SOD1 mutants is non-cell autonomous, with damage within motor neurons driving disease onset and damage within neighboring glial cells (both astrocytes and microglia) driving rapid disease progression. The contribution(s) of mutant SOD1 toxicity within additional cell types, especially oligodendrocytes and their precursors will be tested by deletion of the mutant encoding transgene using cell type specific expression of Cre recombinase. Mechanistically, how mutant SOD1 damages motor neurons, astrocytes and oligodendrocytes will be identified by high throughput sequencing of polysomal mRNAs recovered by ribosomal affinity tagging. This question is of especially high interest for astrocytes, which are known to generate one or more toxicities from their synthesis of ALS causing mutants in SOD1.

Public Health Relevance

Beginning with the discoveries of three genetic causes of the fatal motor neuron disease Amyotrophic Lateral Sclerosis (ALS), this effort seeks to uncover how mutation in these genes triggers the premature death of motor neurons that is the salient feature of this paralytic disease. Key questions to be tackled (whose solution may be central to devising successful therapies for ALS) will be determining the intracellular cascade of damaging events that the mutant proteins provoke and identifying which cell types are damaged by the disease causing mutants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS027036-25A1
Application #
8387977
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gubitz, Amelie
Project Start
1989-04-01
Project End
2017-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
25
Fiscal Year
2012
Total Cost
$492,551
Indirect Cost
$190,187
Name
Ludwig Institute for Cancer Research Ltd
Department
Type
DUNS #
627922248
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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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
Rahdar, Meghdad; McMahon, Moira A; Prakash, Thazha P et al. (2015) Synthetic CRISPR RNA-Cas9-guided genome editing in human cells. Proc Natl Acad Sci U S A 112:E7110-7
Sun, Shuying; Sun, Ying; Ling, Shuo-Chien et al. (2015) Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS. Proc Natl Acad Sci U S A 112:E6993-7002
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
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
Bertuzzi, Stefano; Cleveland, Don W (2015) The curious incident of the translational dog that didn't bark. Trends Cell Biol 25:187-9
Lobsiger, Christian S; Cleveland, Don W (2014) Reply to Woodruff et al.: C1q and C3-dependent complement pathway activation does not contribute to disease in SOD1 mutant ALS mice. Proc Natl Acad Sci U S A 111:E5
Cortes, Constanza J; Ling, Shuo-Chien; Guo, Ling T et al. (2014) Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy. Neuron 82:295-307

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