Neurotrophic effects of progranulin < i > in vivo < /i > in reversing motor neuron defects caused by over or under expression of TDP-43 or FUS

by Babykumari P. Chitramuthu, Denis G. Kay, Andrew Bateman, Hugh P. J. Bennett Progranulin (PGRN) is a glycoprotein with multiple roles in normal and disease states. Mutations within theGRN gene cause frontotemporal lobar degeneration (FTLD). The affected neurons display distinctive TAR DNA binding protein 43 (TDP-43) inclusions. How partial loss of PGRN causes TDP-43 neuropathology is poorly understood. TDP-43 inclusions are also found in affected neurons of patients with other neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In ALS, TDP-43 inclusions are typically also immunoreactive for fused in sarcoma (FUS). Mutations within TDP-43 or FUS are themselves neuropathogenic in ALS and some cases of FTLD. We used the outgrowth of caudal primary motor neurons (MNs) in zebrafish embryos to investigate the interaction of PGRN with TDP-43 and FUSin vivo. As reported previously, depletion of zebrafish PGRN-A (zfPGRN-A) is associated with truncated primary MNs and impaired motor function. Here we found that depletion of zfPGRN-A results in primary MNs outgrowth stalling at the horizontal myoseptum, a line of demarcation separating the myotome into dorsal and ventral compartments that is where the final destination of primary motor is assigned. Successful axonal outgrowth beyond the horizontal myoseptum depends in part upon formation of acetylcholine receptor clusters and this was found to be disorganized upon depletion of zfPGRN-A. P...
Source: PLoS One - Category: Biomedical Science Authors: Source Type: research