Transcriptional targets of amyotrophic lateral sclerosis/frontotemporal dementia protein TDP-43 – meta-analysis and interactive graphical database

Abstract

TDP-43 proteinopathy is the major pathology in amyotrophic lateral sclerosis (ALS) and tau-negative frontotemporal dementia (FTD). Mounting evidence implicates loss of normal TDP-43 RNA processing function as a key pathomechanism. However, the RNA targets of TDP-43 differ by report, and have never been formally collated or compared between models and disease, hampering understanding of TDP-43 function. Here, we conducted re-analysis and meta-analysis of publicly available RNA-sequencing datasets from six TDP-43-knockdown models, and TDP-43-immunonegative neuronal nuclei from ALS/ FTD brain, to identify differentially expressed genes (DEGs) and exon usage (DEU) events. There was little overlap in DEGs between knockdown models, but PFKP, STMN2, CFP, KIAA1324 and TRHDE were common targets and were also differentially expressed in TDP-43-immunonegative neurons. DEG enrichment analysis revealed diverse biological pathways including immune and synaptic functions. Common DEU events in human datasets included well-known targets POLDIP3 and STMN2, and novel targets EXD3, MMAB, DLG5 and GOSR2. Our interactive database https://phpstack-449938-2576646.cloudwaysapps.com/ allows further exploration of TDP-43 DEG and DEU targets. Together, these data identify TDP-43 targets that can be exploited therapeutically or to validate loss-of-function processes.

A panel of TDP-43-regulated splicing events verify loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

“…Therefore, because the role of TDP-43 is context dependent, human-derived transcriptomes are likely to be most suitable for identifying molecular pathways and drug targets relevant to human ALS/FTD. TDP-43 also has distinct sets of molecular targets within a given species but in different cell types (4,11,31,32). While ALS is characterised by the degeneration of motor neurons, it is also recognised as a non-cell autonomous disorder, where non-neuronal cells contribute to neurodegeneration or accelerate disease progression (33)(34)(35)(36).…”

“…Due to TDP-43 regulation of coding mRNAs that encode proteins of diverse and integral functions, numerous pathways may become impaired by dysfunctional TDP-43. This can result in global changes of gene expression that affect both ubiquitous and neuron-specific pathways (4). TDP-43 has been reported to bind to coding transcripts of various functions, including nucleocytoplasmic transport, neurotransmitter release, mitochondrial motility and microtubule stability (9,10,(20)(21)(22)(23)(24).…”

“…Amyotrophic lateral sclerosis (ALS) and tau-negative frontotemporal dementia (FTD) represent the ends of a neurodegenerative spectrum characterized by TDP-43 proteinopathy (1–3). TDP-43 normally functions as an RNA binding protein in the nucleus, but in disease its misfolding and mislocalisation to the cytoplasm causes loss of nuclear function (4–6). Functions of TDP-43 that are lost in disease include RNA regulation and suppression of cryptic exons (7–11).…”

“…Intriguingly, cryptic exons that emerge in human models of TDP-43 loss of function (LOF) and disease are generally not recapitulated in mouse models (4, 11, 31, 32). Therefore, because the role of TDP-43 is context dependent, human-derived transcriptomes are likely to be most suitable for identifying molecular pathways and drug targets relevant to human ALS/FTD.…”

First person – Maize Cao

“… ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Maize Cao is first author on ‘ Transcriptional targets of amyotrophic lateral sclerosis/frontotemporal dementia protein TDP-43 – meta-analysis and interactive graphical database ’, published in DMM. Maize is a PhD student in the lab of Dr Emma Scotter at University of Auckland, New Zealand, Auckland, investigating downstream events of RNA-binding proteins involved in neurodegenerative diseases.…”