NEUROTROPHIN TRAFFICKING IN DEVELOPMENT AND DISEASE

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Date
2015-08-27
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Johns Hopkins University
Abstract
Down syndrome is the most common chromosomal disorder affecting the nervous system in humans. All studies of neuronal defects in Down syndrome have focused on the central nervous system. However, Down syndrome individuals commonly display autonomic dysfunctions, the molecular mechanisms of which are unknown. The sympathetic nervous system is an important branch of the autonomic nervous system that if impaired, contributes to these defects. In this study, I examined the sympathetic nervous system in Down syndrome and the molecular mechanisms that disrupt its development. Normal function of the sympathetic nervous system requires a precise, coordinated developmental program. Using human tissue samples and a trisomic mouse model, I found that the development of the sympathetic nervous system is disrupted in Down syndrome. I found that reduced target innervation and neuronal survival were a result of impaired trafficking of the neurotrophin nerve growth factor (NGF) and its cognate receptor tyrosine kinase, TrkA. The retrograde trafficking of the NGF-TrkA signaling endosome is essential in the development of the sympathetic nervous system. The trafficking of NGF-TrkA is regulated by the serine-threonine phosphatase calcineurin. Calcineurin activity is regulated by the Down syndrome protein Regulator of Calcineurin 1 (RCAN1). Using in vitro adenoviral expression and a transgenic RCAN1 mouse in vivo, I showed that excess RCAN1 inhibits calcineurin activity, impairs TrkA trafficking, and disrupts NGF trophic functions in sympathetic neurons. By reducing RCAN1 dosage to wild type in a Down syndrome mouse model, I showed that RCAN1 overexpression is necessary for TrkA trafficking defects found in DS. Reduction of RCAN1 dosage also ameliorated innervation and neuronal survival defects. This mechanism may also be present in other systems. Basal forebrain cholinergic neurons (BFCNs) also require NGF trafficking for normal development and undergo degeneration in Down syndrome. I provide preliminary evidence that calcineurin also plays a role in BFCN development, likely through regulating NGF-TrkA trafficking. The overexpression of RCAN1 likely inhibits calcineurin activity in this mechanism as well, and contributes to degeneration of the BFCNs in Down syndrome. This study gives insight into how neurotrophins are trafficked during development and how defects in trafficking can lead to disease.
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Keywords
Down's syndrome, sympathetic nervous system, NGF, TrkA, trafficking, RCAN1
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