RT Journal Article
SR Electronic
T1 TDP-43 proteinopathy impairs neuronal mRNP granule mediated postsynaptic local translation and mRNA metabolism
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 589416
DO 10.1101/589416
A1 Chia-En Wong
A1 Kuen-Jer Tsai
YR 2019
UL http://biorxiv.org/content/early/2019/04/04/589416.abstract
AB Local protein synthesis and mRNA metabolism mediated by mRNP granules in the dendrites and the postsynaptic compartments is essential for synaptic remodelling and plasticity in the neuronal cells. Misregulation in these processes caused by TDP-43 proteinopathy lead to neurodegenerative diseases such frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Using biochemical analysis and imaging techniques including super-resolution microscopy, we provide evidences for the first time of the postsynaptic localization of TDP-43 in the mammalian synapses; and we show TDP-43 as a component of neuronal mRNP granules. With activity stimulation and different molecular approaches, we further demonstrate activity-dependent mRNP granule dynamics involving disassembly of mRNP granules, release of mRNAs, and activation of local protein translation as long as impairments in models of TDP-43 proteinopathy. This study elucidates the interplay between TDP-43 and neuronal mRNP granules in normal physiology and TDP-43 proteinopathy in regulation of local protein translation and mRNA metabolism in the postsynaptic compartment.