Neurodegeneration-associated TDP-43 Interacts with Fragile X Mental Retardation Protein (FMRP)/Staufen (STAU1) and Regulates SIRT1 Expression in Neuronal Cells

Abstract

Background: TDP-43 is a major pathological hallmark of several neurodegenerative diseases. Results: TDP-43 interacts with FMRP/STAU1 and binds to the 3Ј-UTR of SIRT1 mRNA to promote its stability. Conclusion: TDP-43, FMRP, and STAU1 form a functionally coordinated complex to regulate the expression of SIRT1. Significance: Adding to our understanding of the mechanistic role of TDP-43 in neurodegenerative diseases.

Proteomic analyses reveal that loss of TDP-43 affects RNA processing and intracellular transport

“…Downregulation of RanBP1, following TDP-43 knockdown, was also observed in SK-Hep1 cell line (Park et al, 2013). Other significantly changed proteins from our list correlated with reported transcriptomic changes, namely vimentin, Pabpc1, Itpr1 (Polymenidou et al, 2011), hemoglobin subunit alpha (Hba1), histone Hist1h2bc (Yu et al, 2012), neuromodulin (Gap43) (Fiesel et al, 2010) and Eno2 (Park et al, 2013). It is however important to be aware that changes in transcript abundance do not necessarily reflect changes in the level of that protein.…”

“…In order to study the effect of TDP-43 depletion on gene expression, several groups used a microarray approach to map transcriptional changes, whether on cell lines (Ayala et al, 2008;Fiesel et al, 2010;Bose et al, 2011;Tollervey et al, 2011;Shiga et al, 2012;Yu et al, 2012;Park et al, 2013;Honda et al, 2014) or animal models (Hazelett et al, 2012), or RNA-seq (Polymenidou et al, 2011). Here we present the effect of TDP-43 depletion at the level of the proteome.…”

Proteomic Analysis of Dynein-Interacting Proteins in Amyotrophic Lateral Sclerosis Synaptosomes Reveals Alterations in the RNA-Binding Protein Staufen1

“…TDP-43 and Staufen1 physically interact, together with Fragile-X mental retardation protein to form a functionally coordinated complex that targets functionally important mRNAs, such as SIRT1, which encodes a protein with neuroprotective functions. In dendrites, this colocalization is increased upon activation (65), while dysregulation of the TDP-43/STAU1/Fragile-X mental retardation protein complex sensitizes neurons to DNA damage and apoptosis (66).…”

UBE2E Ubiquitin-conjugating Enzymes and Ubiquitin Isopeptidase Y Regulate TDP-43 Protein Ubiquitination

“…Outside the nucleus, there is a functional interaction of TDP-43 and SMN in axonal RNA transport granules in neuronal cell cultures (21). Here TDP-43 may participate in complexes containing SMN and other RNA-binding proteins such as fragile X mental retardation protein and Staufen (21,22), pointing to functional roles in axonal mRNA transport and function.…”