The neurodegenerative disease amyotrophic lateral sclerosis (ALS) can be caused by mutations in components of the intracellular motor protein dynein [1]. What, then, are the critical molecules transported by dyneins that are essential for neuronal survival? My colleagues and I have shown that dynein-based transport is required for survival of neurons that depend on target-derived neurotrophic factors. We have shown that this reflects the role of axonal dynein in mediating transport of activated neurotrophin receptors (Trks) within large signaling endosomes. Therefore, we hypothesize that ALS may result from deficiencies in long-range neurotrophic factor signaling, and that restoring these retrograde signals will provide an effective therapeutic approach to the disease. We have identified a set of genes that are preferentially induced by neurotrophin stimulation of distal axons (retrograde signals) rather than by stimulation of cell bodies . (anterograde signals), a set that we designate as retrograde response genes. The retrograde response gene set contains several members that are likely to protect cells from progressive neurodegeneration, including the anti-apoptotic gene bclw and the survival-promoting factor IGF-1. In the proposed studies we will build on our identification of spatially selective neurotrophin responses to determine the mechanisms and functions of specialized retrograde signals. We have three aims. 1. To determine the mechanisms responsible for induction of retrograde response genes by target-derived , neurotrophins, using both motor and sensory neurons grown in compartmented cultures. 2. To determine the functions of retrograde response genes in developing and mature neurons. We will focus on bclw, a poorly understood pro-survival bc!2 family member that is preferentially expressed in the mature nervous system, and can protect diverse neurons from apoptotic stimuli. 3. To test the hypothesis that mutations in dynein that cause ALS do so by interfering with the signaling pathways that induce bclw and other retrograde response genes. We will determine whether expression of these genes protects motor neurons from progressive degeneration. Understanding the mechanism and significance of long distance survival pathways may lead to new therapeutic approaches for ALS and other devastating neurodegenerative disorders.
| Pease-Raissi, Sarah E; Pazyra-Murphy, Maria F; Li, Yihang et al. (2017) Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration. Neuron 96:373-386.e6 |
| Cosker, Katharina E; Fenstermacher, Sara J; Pazyra-Murphy, Maria F et al. (2016) The RNA-binding protein SFPQ orchestrates an RNA regulon to promote axon viability. Nat Neurosci 19:690-696 |
| Tasdemir-Yilmaz, Ozge E; Segal, Rosalind A (2016) There and back again: coordinated transcription, translation and transport in axonal survival and regeneration. Curr Opin Neurobiol 39:62-8 |
| Balastik, Martin; Zhou, Xiao Zhen; Alberich-Jorda, Meritxell et al. (2015) Prolyl Isomerase Pin1 Regulates Axon Guidance by Stabilizing CRMP2A Selectively in Distal Axons. Cell Rep 13:812-828 |
| Pease, Sarah E; Segal, Rosalind A (2014) Preserve and protect: maintaining axons within functional circuits. Trends Neurosci 37:572-82 |
| Cosker, Katharina E; Segal, Rosalind A (2014) Neuronal signaling through endocytosis. Cold Spring Harb Perspect Biol 6: |
| Cosker, Katharina E; Pazyra-Murphy, Maria F; Fenstermacher, Sara J et al. (2013) Target-derived neurotrophins coordinate transcription and transport of bclw to prevent axonal degeneration. J Neurosci 33:5195-207 |
| Fainzilber, Mike; Budnik, Vivian; Segal, Rosalind A et al. (2011) From synapse to nucleus and back again--communication over distance within neurons. J Neurosci 31:16045-8 |
| Courchesne, Stephanie L; Karch, Christoph; Pazyra-Murphy, Maria F et al. (2011) Sensory neuropathy attributable to loss of Bcl-w. J Neurosci 31:1624-34 |
| Courchesne, Stephanie L; Pazyra-Murphy, Maria F; Lee, Daniel J et al. (2011) Neuromuscular junction defects in mice with mutation of dynein heavy chain 1. PLoS One 6:e16753 |
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