Peptidylprolyl isomerase A governs TARDBP function and assembly in heterogeneous nuclear ribonucleoprotein complexes

Lauranzano, Eliana; Pozzi, Silvia; Pasetto, Laura; Stucchi, Riccardo; Massignan, Tania; Paolella, Katia; Mombrini, Melissa; Nardo, Giovanni; Lunetta, Christian; Corbo, Massimo; Mora, Gabriele; Bendotti, Caterina; Bonetto, Valentina

doi:10.1093/brain/awv005

Cited by 41 publications

(80 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Proteomic studies of cellular proteins that bind to hydrogel droplets formed from the LC domains of both hnRNPA2 and FUS revealed retention of PPIA, the most abundant isoform of a family of peptidyl-prolyl cis-trans isomerase enzymes. PPIA has been reported to interact with RNA granule proteins upon biochemical fractionation (Lauranzano et al ., 2015), and antibodies to the enzyme revealed co-localization with stress granules (Figure S3). We thus reasoned that the PPIA enzyme might affect the structure of hnRNPA2 fibers by facilitating cis-trans interconversion of the peptide bonds of proline residue 319 or 326 of the hnRNPA2 polypeptide.…”

Section: Resultsmentioning

confidence: 99%

The LC Domain of hnRNPA2 Adopts Similar Conformations in Hydrogel Polymers, Liquid-like Droplets, and Nuclei

Xiang

Kato

et al. 2015

Cell

276

300

View full text Add to dashboard Cite

SUMMARY Many DNA and RNA regulatory proteins contain polypeptide domains that are unstructured when analyzed in cell lysates. These domains are typified by an over-representation of a limited number of amino acids and have been termed prion-like, intrinsically disordered or low complexity (LC) domains. When incubated at high concentration, certain of these LC domains polymerize into labile, amyloid-like fibers. Here we report methods allowing the generation of a molecular footprint of the polymeric state of the LC domain of hnRNPA2. By deploying this footprinting technique to probe the structure of the native hnRNPA2 protein present in isolated nuclei, we offer evidence that its LC domain exists in a similar conformation as that described for recombinant polymers of the protein. These observations favor biologic utility to the polymerization of LC domains in the pathway of information transfer from gene to message to protein.

show abstract

Section: Resultsmentioning

confidence: 99%

The LC Domain of hnRNPA2 Adopts Similar Conformations in Hydrogel Polymers, Liquid-like Droplets, and Nuclei

Xiang

Kato

et al. 2015

Cell

276

300

View full text Add to dashboard Cite

show abstract

“…We originally identified it as a candidate protein biomarker in PBMC of ALS patients with classical disease onset, where it is upregulated also in association with disease progression (Nardo et al, 2011). We next found that mutant SOD1 and TDP-43 are substrates of PPIA (Lauranzano et al, 2015). In fact, in absence of PPIA increased levels of mutant SOD1 and TDP-43 were recovered in the aggregates isolated from the spinal cord of SOD1 G93A mice that had also an anticipation of the onset and an acceleration of the disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…These phenotypic biomarkers are: PPIA, HSP90, GRP78, and DJ-1. Polyclonal anti-peptidyl-prolyl cis-trans isomerase A is ubiquitously expressed, with the highest expression in neurons and motor neurons (Lauranzano et al, 2015). It is a peptidylprolyl cis/trans isomerase and, as a foldase, it accelerates the ratelimiting steps along the folding pathway, but it also acts as a classical molecular chaperone (Fischer et al, 1989;Freskgard et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis

Filareti

Luotti

Pasetto

et al. 2017

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive upper and lower motor neuron degeneration. One of the peculiar clinical characteristics of ALS is the wide distribution in age of onset, which is probably caused by different combinations of intrinsic and exogenous factors. We investigated whether these modifying factors are converging into common pathogenic pathways leading either to an early or a late disease onset. This would imply the identification of phenotypic biomarkers, that can distinguish the two populations of ALS patients, and of relevant pathways to consider in a therapeutic intervention. Toward this aim a differential proteomic analysis was performed in peripheral blood mononuclear cells (PBMC) from a group of 16 ALS patients with an age of onset ≤55 years and a group of 16 ALS patients with an age of onset ≥75 years, and matched healthy controls. We identified 43 differentially expressed proteins in the two groups of patients. Gene ontology analysis revealed that there was a significant enrichment in annotations associated with protein folding and response to stress. We next validated a selected number of proteins belonging to this functional group in 85 patients and 83 age- and sex-matched healthy controls using immunoassays. The results of the validation study confirmed that there was a decreased level of peptidyl-prolyl cis-trans isomerase A (also known as cyclophilin A), heat shock protein HSP 90-alpha, 78 kDa glucose-regulated protein (also known as BiP) and protein deglycase DJ-1 in PBMC of ALS patients with an early onset. Similar results were obtained in PBMC and spinal cord from two SOD1G93A mouse models with an early and late disease onset. This study suggests that a different ability to upregulate proteins involved in proteostasis, such as foldase and chaperone proteins, may be at the basis of a different susceptibility to ALS, putting forward the development of therapeutic approaches aiming at boosting the protein quality control system.

show abstract

“…Peptidylprolyl isomerase A (PPIA), also known as cyclophilin A, is a functional interacting partner of TDP-43. PPIA regulates expression of known TDP-43 RNA targets and is necessary for the assembly of TARDBP in hnRNP complexes [14]. Several other genes, including progranulin (PGRN), valosin-containing protein (VCP), and C9ORF72, are also reported to relate to TDP-43 proteinopathies [15][16][17][18].…”

Section: Biochemical Characters Of Tdp-43mentioning

confidence: 99%

The Role of TDP-43 in Alzheimer’s Disease

Chang

Tan

et al. 2015

Mol Neurobiol

View full text Add to dashboard Cite

The transactive response DNA binding protein (TDP-43) has long been characterized as a main hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U, also known as FTLD-TDP). Several studies have indicated TDP-43 deposits in Alzheimer's disease (AD) brains and have robust connection with AD clinical phenotype. FTLD-U, which was symptomatically connected with AD, may be predictable for the comprehension of the role TDP-43 in AD. TDP-43 may contribute to AD through both β-amyloid (Aβ)-dependent and Aβ-independent pathways. In this article, we summarize the latest studies concerning the role of TDP-43 in AD and explore TDP-43 modulation as a potential therapeutic strategy for AD. However, to date, little of pieces of the research on TDP-43 have been performed to investigate the role in AD; more investigations need to be confirmed in the future.

show abstract

Peptidylprolyl isomerase A governs TARDBP function and assembly in heterogeneous nuclear ribonucleoprotein complexes

Cited by 41 publications

References 61 publications

The LC Domain of hnRNPA2 Adopts Similar Conformations in Hydrogel Polymers, Liquid-like Droplets, and Nuclei

The LC Domain of hnRNPA2 Adopts Similar Conformations in Hydrogel Polymers, Liquid-like Droplets, and Nuclei

Decreased Levels of Foldase and Chaperone Proteins Are Associated with an Early-Onset Amyotrophic Lateral Sclerosis

The Role of TDP-43 in Alzheimer’s Disease

Contact Info

Product

Resources

About