Profiling the genes affected by pathogenic TDP‐43 in astrocytes

Abstract

Mutation in TAR DNA binding protein 43 (TDP-43) is a causative factor of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Neurodegeneration may not require the presence of pathogenic TDP-43 in all types of relevant cells. Rather, expression of pathogenic TDP-43 in neurons or astrocytes alone is sufficient to cause cell-autonomous or non-cell-autonomous neuron death in transgenic rats. How pathogenic TDP-43 in astrocytes causes non-cell-autonomous neuron death, however, is not clear. Here, we examined the effect of pathogenic TDP-43 on gene expression in astrocytes. Microarray assay revealed that pathogenic TDP-43 in astrocytes preferentially altered expression of the genes encoding secretory proteins. Whereas neurotrophic genes were down-regulated, neurotoxic genes were up-regulated. Representative genes Lcn2 and Chi3L1 were markedly up-regulated in astrocytes from primary culture and intact transgenic rats. Further, synthetic Chi3L1 induced neuron death in a dose-dependent manner. Our results suggest that TDP-43 pathogenesis is associated with the simultaneous induction of multiple neurotoxic genes in astrocytes, which may synergistically produce adverse effects on neuronal survival and contribute to non-cell-autonomous neuron death.

Chitinase 3-Like 1 Promotes Candida albicans Killing and Preserves Corneal Structure and Function by Controlling Host Antifungal Responses

“…CHI3L1 is a multifunctional protein that has been implicated as a critical regulator of anti-infectious and adaptive T helper 2 (Th2) responses (18,24). Using a C. albicans keratitis model, we tested the hypothesis that CHI3L1 plays a role in antifungal responses.…”

“…CHI3L1 can be readily detected in the circulation of normal individuals. However, its expression is dysregulated in the circulation and/or tissues from patients with a variety of diseases characterized by inflammation and/or tissue remodeling (24). Studies using CHI3L1 knockout mice demonstrated exacerbated inflammation, hemorrhage, and lung injury following Streptococcus pneumoniae infection, indicating the protective role of CHI3L1 in promoting bacterial clearance and augmenting host tolerance (25).…”

Invited Review: Decoding the pathophysiological mechanisms that underlieRNAdysregulation in neurodegenerative disorders: a review of the current state of the art

“…Several thousand TDP-43 and FUS RNA-binding sites have been characterized on pre-mRNA molecules, including those involved in splicing functions of long pre-mRNAs essential to neuronal development and integrity [176,182,183]. Alternative splicing of pre-mRNAs was found to be broadly altered in TDP-43 and FUS-related ALS, leading to the dysregulation of normal neuronal gene expression with the synthesis of thousands of aberrantly spliced mRNA molecules [182,[184][185][186][187][188][189]. In particular, these recent transcriptome studies highlighted an alteration of levels and/or splicing of genes involved in RNA processing, synthesis of neurotrophic factors and synaptic function.…”

“…Disruption of GEMs is observed in both SMA and TDP-43/FUS-related ALS [191,192], and concordantly, the integrity of spliceosomes was found to be altered in both diseases [121]. Expression level alteration/sequestration of RNAprocessing factors such as RRM-containing splicing factors (hnRNPs, SRSFs) further leads to large splicing alterations in SMA [123][124][125], TDP-43/FUS-related ALS [182,[184][185][186][187][188][189] and C9ORF72-related ALS [153,154].…”

p.N345K mutation in TARDBP in a patient with familial amyotrophic lateral sclerosis: An autopsy case

“…It is also unclear how the abnormal astrocytic TDP-43 expression could have contributed to neuronal death, but our patient's case may provide clues as to the mechanism associated with non-cell autonomous neuronal death in ALS. 29 In conclusion, whether the glial (especially astrocytic) accentuation of TDP-43 pathology in patients with p. N345K mutation occurs by chance, or whether the pathogenic mutation causes preferential accumulation of TDP-43 in glia is still not resolved. Further pathological investigations are needed to clarify whether the p.N345K mutation has the potential to accentuate glial TDP-43 pathology.…”