Amyotrophic lateral sclerosis (ALS) is a uniformly lethal, age-dependent neurodegenerative disorder with a typical survival of 2-5 years. With the possible exception of reduced numbers of copies of the SMN gene, or the presence of the SOD1A4V gene mutation, genetic factors that influence survival in ALS have not been described. We recently reported that survival in sporadic ALS is enhanced by genetic variants that reduce expression of KIFAP3, a protein constituent of a kinesin II complex that mediates fast anterograde axonal transport. Homozygotes for the favorable allele have a survival advantage of 14.0 months, a substantial improvement (~42%) that surpasses the magnitude of benefit of the single drug (riluzole) that is FDA approved for ALS in ALS. A recent study documents that KIFAP3 binds misfolded SOD1G93A in ALS mice and is co-localized with the mutant SOD1 protein in aggregates both in the SOD1G93A mouse and in spinal cords of ALS patients bearing mutations in the SOD1 gene. These findings support the view that axonal transport proteins, and KIFAP3 in particular, are determinants of motor neuron viability. This proposal will investigate the mechanisms by which decreased expression of KIFAP3 increases survival in ALS.
The Specific Aims of this proposal are to: (1) Analyze the interactions between KIFAP3, SOD1 and other cargoes in human sporadic ALS spinal cords. Hypothesis: Misfolded, wild-type SOD1 binds to KIFAP3 in sporadic ALS but not control spinal cords. (2) Determine the effect of reduced KIFAP3 expression on motor neuron viability and survival in transgenic SOD1G93A mice. Hypothesis: By analogy with survival in human ALS, motor neuron viability and survival in transgenic ALS mice will be enhanced by reduced expression of KIFAP3. (3) Analyze the interactions between KIFAP3, SOD1 and other cargoes in spinal cord from ALS and control mice with normal and reduced levels of KIFAP3. Hypothesis: Decreased expression of KIFAP3 will alter the types and quantities of cargoes transported by KIFAP3. (4) Determine the influence of altered expression levels of KIFAP3 on axonal transport rates in embryonic motor neurons from ALS and control mice. Hypothesis: Altered levels of KIFAP3 expression are not determinants of axonal transport rates. Our proposed studies will elucidate the mechanisms whereby KIFAP3 expression modulates survival in ALS. In the long term, understanding how KIFAP3 influences survival will facilitate the development of therapies to extend the lifespan of ALS patients.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a uniformly lethal, age-dependent neurodegenerative disorder with a typical survival of 2 to 5 years. Through our efforts, we have identified a gene which can influence the survival advantage of sporadic ALS by 14.0 months, a substantial increment (42%) in this disease. The purpose of this proposal is to understand how this gene influences survival, which will aid in the development of treatment strategies to extend the lifespan of patients afflicted with ALS.
|Peters, Owen M; Cabrera, Gabriela Toro; Tran, Helene et al. (2015) Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice. Neuron 88:902-9|
|Smith, Bradley N; Vance, Caroline; Scotter, Emma L et al. (2015) Novel mutations support a role for Profilin 1 in the pathogenesis of ALS. Neurobiol Aging 36:1602.e17-27|
|Peters, Owen M; Ghasemi, Mehdi; Brown Jr, Robert H (2015) Emerging mechanisms of molecular pathology in ALS. J Clin Invest 125:1767-79|
|van Doormaal, Perry T C; Ticozzi, Nicola; Gellera, Cinzia et al. (2014) Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study. Neurobiol Aging 35:2420.e13-4|
|Smith, Bradley N; Ticozzi, Nicola; Fallini, Claudia et al. (2014) Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron 84:324-31|
|Seijffers, Rhona; Zhang, Jiangwen; Matthews, Jonathan C et al. (2014) ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation. Proc Natl Acad Sci U S A 111:1622-7|
|Sreedharan, Jemeen; Brown Jr, Robert H (2013) Amyotrophic lateral sclerosis: Problems and prospects. Ann Neurol 74:309-16|
|Ingre, Caroline; Landers, John E; Rizik, Naji et al. (2013) A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts. Neurobiol Aging 34:1708.e1-6|
|van Blitterswijk, Marka; Wang, Eric T; Friedman, Brad A et al. (2013) Characterization of FUS mutations in amyotrophic lateral sclerosis using RNA-Seq. PLoS One 8:e60788|
|Tiloca, Cinzia; Ticozzi, Nicola; Pensato, Viviana et al. (2013) Screening of the PFN1 gene in sporadic amyotrophic lateral sclerosis and in frontotemporal dementia. Neurobiol Aging 34:1517.e9-10|
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