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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gubitz, Amelie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ludwig Institute for Cancer Research Ltd
La Jolla
United States
Zip Code
Winkler, Ethan A; Sengillo, Jesse D; Sagare, Abhay P et al. (2014) Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc Natl Acad Sci U S A 111:E1035-42
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
Ling, Shuo-Chien; Polymenidou, Magdalini; Cleveland, Don W (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416-38
Foust, Kevin D; Salazar, Desirée L; Likhite, Shibi et al. (2013) Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. Mol Ther 21:2148-59
Parone, Philippe A; Da Cruz, Sandrine; Han, Joo Seok et al. (2013) Enhancing mitochondrial calcium buffering capacity reduces aggregation of misfolded SOD1 and motor neuron cell death without extending survival in mouse models of inherited amyotrophic lateral sclerosis. J Neurosci 33:4657-71
Vande Velde, Christine; McDonald, Karli K; Boukhedimi, Yasmin et al. (2011) Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset. PLoS One 6:e22031
Li, Quan; Vande Velde, Christine; Israelson, Adrian et al. (2010) ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import. Proc Natl Acad Sci U S A 107:21146-51
Lobsiger, Christian S; Boillee, Severine; McAlonis-Downes, Melissa et al. (2009) Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice. Proc Natl Acad Sci U S A 106:4465-70
Garcia, Michael L; Rao, Mala V; Fujimoto, Jiro et al. (2009) Phosphorylation of highly conserved neurofilament medium KSP repeats is not required for myelin-dependent radial axonal growth. J Neurosci 29:1277-84
Zhong, Zhihui; Ilieva, Hristelina; Hallagan, Lee et al. (2009) Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J Clin Invest 119:3437-49

Showing the most recent 10 out of 53 publications