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Retrograde nerve growth factor signaling abnormalities in familial dysautonomia.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2020 May 01; Vol. 130 (5), pp. 2478-2487. - Publication Year :
- 2020
-
Abstract
- Familial dysautonomia (FD) is the most prevalent form of hereditary sensory and autonomic neuropathy (HSAN). In FD, a germline mutation in the Elp1 gene leads to Elp1 protein decrease that causes sympathetic neuron death and sympathetic nervous system dysfunction (dysautonomia). Elp1 is best known as a scaffolding protein within the nuclear hetero-hexameric transcriptional Elongator protein complex, but how it functions in sympathetic neuron survival is very poorly understood. Here, we identified a cytoplasmic function for Elp1 in sympathetic neurons that was essential for retrograde nerve growth factor (NGF) signaling and neuron target tissue innervation and survival. Elp1 was found to bind to internalized TrkA receptors in an NGF-dependent manner, where it was essential for maintaining TrkA receptor phosphorylation (activation) by regulating PTPN6 (Shp1) phosphatase activity within the signaling complex. In the absence of Elp1, Shp1 was hyperactivated, leading to premature TrkA receptor dephosphorylation, which resulted in retrograde signaling failure and neuron death. Inhibiting Shp1 phosphatase activity in the absence of Elp1 rescued NGF-dependent retrograde signaling, and in an animal model of FD it rescued abnormal sympathetic target tissue innervation. These results suggest that regulation of retrograde NGF signaling in sympathetic neurons by Elp1 may explain sympathetic neuron loss and physiologic dysautonomia in patients with FD.
- Subjects :
- Animals
Dysautonomia, Familial genetics
Dysautonomia, Familial pathology
Germ-Line Mutation
Humans
Intracellular Signaling Peptides and Proteins genetics
Intracellular Signaling Peptides and Proteins metabolism
Mice
Mice, Transgenic
Nerve Growth Factor genetics
Neurons pathology
Protein Tyrosine Phosphatase, Non-Receptor Type 6 genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 6 metabolism
Receptor, trkA genetics
Receptor, trkA metabolism
Sympathetic Nervous System pathology
Dysautonomia, Familial metabolism
Nerve Growth Factor metabolism
Neurons metabolism
Signal Transduction
Sympathetic Nervous System metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 130
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 32281946
- Full Text :
- https://doi.org/10.1172/JCI130401