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Stress-induced condensation of TDP-43 in the nucleus

ABSTRACT: TDP-43 is an RNA-binding protein ubiquitously dysregulated in neurodegeneration. We found that under stress conditions, TDP-43 undergoes reversible condensation in the nucleus of cultured cells including human neurons. These condensates (“TCs”) are non-liquid assemblies with low dynamic properties. Their proteomic analysis and subsequent comparison with the normal (soluble) TDP-43 interactome revealed that upon condensate partitioning, TDP-43 dissociates from its normal protein binding partners. We propose that the main function of TCs is rapid but reversible inactivation of TDP-43 during stress. This can help fine-tune the splicing patterns under stress to enable efficient stress response and survival.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Tatyana Shelkovnikova

PROVIDER: PXD052963 | JPOST Repository | Mon Jun 10 00:00:00 BST 2024

REPOSITORIES: jPOST

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			Action	DRS
	GFP_1.raw	Raw
	GFP_2.raw	Raw
	Rachel%20Hodgson%20110823_GFP1.xlsx	Xlsx
	Rachel%20Hodgson%20110823_GFP2.xlsx	Xlsx
	Rachel%20Hodgson%20110823_TC2-1.xlsx	Xlsx

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Project description:TDP-43, a DNA/RNA binding protein involved in RNA transcription and splicing has been associated with the pathophysiology of neurodegenerative diseases, including ALS. However, the function of TDP-43 in motor neurons remains undefined. Here, we employ both gain- and loss-of-function approaches to determine roles of TDP-43 in motor neurons. Mice expressing human TDP-43 in neurons exhibited growth retardation and premature death that are characterized by abnormal intranuclear inclusions comprised of TDP-43 and Fused in Sarcoma (FUS), and massive accumulation of mitochondria in TDP-43-negative cytoplasmic inclusions in motor neurons, lack of mitochondria in motor axon terminals and immature neuromuscular junctions. Whereas elevated level of TDP-43 disrupts the normal nuclear distribution of Survival Motor Neuron (SMN)-associated Gemini of coiled bodies (GEMs) in motor neurons, its absence prevents the formation of GEMs in the nuclei of these cells. Moreover, transcriptome-wide deep sequencing analysis revealed that decrease in abundance of neurofilament transcripts contributed to the reduction of caliber of motor axons in TDP-43 mice. In concert, our findings indicate that TDP-43 participates in pathways critical for motor neuron physiology, including those that regulate the normal distributions of SMN-associated GEMs in the nucleus and mitochondria in the cytoplasm. Human TDP-43 coding region were inserted into pThy1.2 expression cassette and subsequently injected into C57BL/6;SJL hybrid mouse embryos to make human TDP-43 transgenic mice

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2011-03-03 | E-GEOD-27201 | biostudies-arrayexpress

Loss of nuclear TDP-43 in ALS causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurons [NSC34]

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