This proposal focuses on the role of receptor tyrosine kinases in rendering motor neurons susceptible to neurodegenerative insults. TrkB is activated by its ligand, brain-derived neurotrophic factor. Several independent laboratories show that blocking TrkB activation in vitro can protect neurons from specific insults. Despite the heresy of these observations, we have seen the same phenomenon in vitro and in a specific in vivo circumstance.
In specific aim #1 we will investigate the temporal aspect of this process by putting the mutant SOD mouse on a TrkBF616A background. TrkBF616A can be specifically antagonized by the orally active, blood brain barrier permeable agent, 1NMPP1. A second receptor tyrosine kinase of interest is the Insulin/Insulin-like growth factor receptor (IGF-R). In model organisms (and recently in mice) a conserved stress resistance pathway is evoked when the activity of the IGF-R is reduced. The FOXO3a transcription factor plays a key role in this process in worms and flies, but its function in vertebrates is unknown.
In specific aim #2, we will determine if loss of FOXO3a ameliorates or exacerbates the mutant SOD mouse motor neuron disease. In the course of our investigations of FOXO3a, we found a marine sponge compound (Psammaplysene A, PA) that promotes nuclear localization of the transcription factor and is broadly neuroprotective in in vitro and in vivo models of neurodegeneration. While the evidence is strong that the compound works through FOXO3a, the precise molecular target is not known.
In specific aim #3, several approaches will be employed to find the target and pathway through which PA acts. Overall this work attempts to find new disease modifiers that slow the progression of motor neuron disease. If successful, new therapeutic targets will emerge.
It is not known why specific neuronal populations are vulnerable to the toxic effects of neurodegenerative stimuli. In this proposal we will examine the role played by two signaling pathways in rendering motor neurons susceptible to insults relevant to Lou Gehrig's disease. In addition, we have identified a small molecule with remarkable neuroprotective activity. In this proposal we will determine the molecular target of this molecule and the signaling pathway through which it operates.
|Boccitto, M; Doshi, S; Newton, I P et al. (2016) Opposing actions of the synapse-associated protein of 97-kDa molecular weight (SAP97) and Disrupted in Schizophrenia 1 (DISC1) on Wnt/Î²-catenin signaling. Neuroscience 326:22-30|
|Zhai, Jinbin; Zhang, Lei; Mojsilovic-Petrovic, Jelena et al. (2015) Inhibition of Cytohesins Protects against Genetic Models of Motor Neuron Disease. J Neurosci 35:9088-105|
|Zhang, L; Hsu, F-C; Mojsilovic-Petrovic, J et al. (2015) Structure-function analysis of SAP97, a modular scaffolding protein that drives dendrite growth. Mol Cell Neurosci 65:31-44|
|Burguete, Alondra Schweizer; Almeida, Sandra; Gao, Fen-Biao et al. (2015) GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function. Elife 4:e08881|
|Jablonski, Angela M; Lamitina, Todd; Liachko, Nicole F et al. (2015) Loss of RAD-23 Protects Against Models of Motor Neuron Disease by Enhancing Mutant Protein Clearance. J Neurosci 35:14286-306|
|Lim, Maria A; Bence, Kendra K; Sandesara, Ishani et al. (2014) Genetically altering organismal metabolism by leptin-deficiency benefits a mouse model of amyotrophic lateral sclerosis. Hum Mol Genet 23:4995-5008|
|Jablonski, Angela M; Kalb, Robert G (2013) GluA1 promotes the activity-dependent development of motor circuitry in the developing segmental spinal cord. Ann N Y Acad Sci 1279:54-9|
|Moronetti Mazzeo, Lorenza E; Dersh, Devin; Boccitto, Marco et al. (2012) Stress and aging induce distinct polyQ protein aggregation states. Proc Natl Acad Sci U S A 109:10587-92|
|Lim, M A; Selak, M A; Xiang, Z et al. (2012) Reduced activity of AMP-activated protein kinase protects against genetic models of motor neuron disease. J Neurosci 32:1123-41|
|Boccitto, Marco; Lamitina, Todd; Kalb, Robert G (2012) Daf-2 signaling modifies mutant SOD1 toxicity in C. elegans. PLoS One 7:e33494|
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