TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD

Abstract

Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterised by TDP-43 pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here, we have created a novel TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43Q331K mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically, TDP-43 autoregulation is perturbed leading to a gain of TDP-43 function, and altered splicing of Mapt, another pivotal dementia gene. Furthermore, a novel approach to stratify transcriptomic data by phenotype in differentially affected mutant mice reveals 471 changes linked with improved behaviour. These changes include downregulation of two known modifiers of neurodegeneration, Atxn2 and Arid4a, and upregulation of myelination and translation genes. With one base change in murine Tardbp, this study identifies TDP-43 misregulation as a pathogenic mechanism that may underpin ALS-FTD, and exploits phenotypic heterogeneity to yield candidate suppressors of neurodegenerative disease.

Review: Neuropathology of non‐tau frontotemporal lobar degeneration

“…Although TDP‐43 pathology seems to be a consistent feature in these cases, the pattern of FTLD‐TDP is not consistent, often difficult to classify and may be combined with a more complex proteinopathy . Some of the clinical and pathological variation associated with TARDBP mutations may reflect recent findings that different mutations may have different pathomechanisms, including both loss of function and gain of RNA splicing activity .…”

Abnormal TDP ‐43 function impairs activity‐dependent BDNF secretion, synaptic plasticity, and cognitive behavior through altered Sortilin splicing

“…From the point of view of network theory, RBPs can be thought of as highly connected hubs, linked to hundreds or thousands of other proteins. Numerous studies have taken advantage of different genome-wide approaches to identify possible TDP-43 targets important in ALS/FTLD pathophysiology [e.g., (Polymenidou et al, 2011;Sephton et al, 2011;Xiao et al, 2011;White et al, 2018)]. Such networks, also known as scale-free networks, are very resistant to accidental failures, but vulnerable to coordinated attacks on their principal hubs.…”

“…B TDP-43 intensity in cell nuclei of untransduced or TDP-43 12xQN-infected hippocampal neurons normalized to mean nuclear intensity in untransduced neurons. Two recent studies generated knock-in mice carrying a Q331K substitution, equivalent to a mutation found in human patients, and found mRNA splicing patterns in TDP-43 target genes consistent with enhanced TDP-43 activity, suggesting a gain-of-function mechanism (Fratta et al, 2018;White et al, 2018). Student's ttest; **P < 0.01.…”

“…Results are presented as average AE SEM (N = 3 independent experiments; n = 3 wells per condition in each experiment). Intriguingly, although Q331K knock-in mice showed reduced levels of Sort1 mRNA containing exon 17b, they displayed significantly elevated levels of mutant Tardbp mRNA and TDP-43 protein, by as much as 45% (White et al, 2018). C Expression of Tardbp (left), total Sort1 (center), and exon 17b Sort1 (right) mRNAs quantified by qPCR in hippocampal neurons untransduced (control) or infected with lentiviruses expressing Tardbp shRNA or human TDP-43 12xQN constructs.…”

Review: Molecular pathology of frontotemporal lobar degenerations

“…[155,156] Tau/MAPT In patients, the majority of TDP-43-positive inclusions are independent of tau-positive structures. However, TDP-43 has been shown to inhibit Tau expression by promoting mRNA instability and mutant TDP-43 Q331K mice display a specific increase in inclusion of MAPT exons 2 and 3 [157][158][159] UBQLN2…”