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Trafficking the Target-Derived Signals of Neurotrophic Factors: Implications for Normal and Degenerating Neurons

By William Mobley

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Elucidating the cellular mechanisms that build and maintain synaptic connections is required for understanding normal and abnormal nervous system function. The neurotrophins (NTs) are a family of neurotrophic factors that act to influence the development and maintenance of neurons. Understanding their physiological roles requires that we elucidate how NT signals generated in the target of innervation are moved retrogradely to cell bodies to regulate cytosolic and nuclear events. We and others have provided evidence that NT signals are transmitted via endocytosis of complexes containing the NT bound to its activated receptor followed by retrograde transport of the ``signaling endosome'' thus formed. We are testing the hypothesis that failed retrograde transport of NT signals contributes to neurodegeneration. Objective: To explore the mechanisms for retrogradely transporting NT signals and to examine them in mouse models of neurodegeneration. Methods: In studies in vitro and in vivo, we have examined and isolated endosomal membranes that contain nerve growth factor (NGF) and its receptors and have shown that NGF signals arise from these organelles. Results: Our studies have shown that: 1) signaling endosomes arise from membranes in which many of the component signaling molecules are preassembled; 2) these endosomes feature on their cytosolic surface a membrane-based array of signaling molecules; 3) they arise in clathrin-coated membranes and are moved via dynein and microtubules from clathrin-coated vesicles to early endosomes; and 4) early endosomes carry NGF signals from axon terminals to the cell bodies of neurons by fast retrograde transport. Pointing to the potential physiological importance of signaling endosomes, we discovered that failed retrograde transport of NGF was linked to the degeneration of basal forebrain cholinergic neurons (BFCNs) in the Ts65Dn mouse model of Down syndrome (DS). In very recent studies in other models of DS, we have identified a gene whose presence in three copies is necessary for producing the dramatic defect in NGF transport in Ts65Dn. Conclusions: There is compelling evidence that signaling endosomes are responsible for the retrograde movement of robust NT signals in axons. Our findings raise the possibility that failure to make or traffic signaling endosomes contributes to neurodegeneration.

Citation: Jean-Dominique Delcroix, Ahmad Salehi, William Mobley. Trafficking the Target-Derived Signals of Neurotrophic Factors: Implications for Normal and Degenerating Neurons. NeuroBiology of Aging, Volume 25, Number S2 , July 2004, Page 67

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