The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis

Bampton, Alexander; Gittings, Lauren M.; Fratta, Pietro; Lashley, Tammaryn; Gatt, Ariana

doi:10.1007/s00401-020-02203-0

Cited by 85 publications

(82 citation statements)

References 220 publications

(306 reference statements)

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“…The interactome of ALS-associated genes shares somewhat similar RNA-binding proteins. Each interactome of the hnRNP family or key pathological genes is associated with ALS, including TARDBP , C9orf72 , and FUS [ 151 ]. In the case of FUS, several hnRNPs, including HNRNPA1, R, and SYNCRIP, have been shown to co-accumulate in FUS-positive pathological inclusions [ 151 , 152 ].…”

Section: Discussionmentioning

confidence: 99%

“…Each interactome of the hnRNP family or key pathological genes is associated with ALS, including TARDBP , C9orf72 , and FUS [ 151 ]. In the case of FUS, several hnRNPs, including HNRNPA1, R, and SYNCRIP, have been shown to co-accumulate in FUS-positive pathological inclusions [ 151 , 152 ]. Many other hnRNPs, including HNRNPD, L, and I, have also been found within FUS-negative pathological inclusions [ 151 ].…”

Section: Discussionmentioning

confidence: 99%

“…In the case of FUS, several hnRNPs, including HNRNPA1, R, and SYNCRIP, have been shown to co-accumulate in FUS-positive pathological inclusions [ 151 , 152 ]. Many other hnRNPs, including HNRNPD, L, and I, have also been found within FUS-negative pathological inclusions [ 151 ]. RNA foci derived from C9orf72 hexanucleotide repeat expansion have been associated with HNRNPH1, HNRNPH3, HNRNPF, HNRNPA1, HNRNPA3, and other nuclear speckle related RNA-binding proteins [ 151 , 153 ].…”

Section: Discussionmentioning

confidence: 99%

“…Many other hnRNPs, including HNRNPD, L, and I, have also been found within FUS-negative pathological inclusions [ 151 ]. RNA foci derived from C9orf72 hexanucleotide repeat expansion have been associated with HNRNPH1, HNRNPH3, HNRNPF, HNRNPA1, HNRNPA3, and other nuclear speckle related RNA-binding proteins [ 151 , 153 ]. The poly-GR and poly-PR interactome also somewhat similarly overlaps with other interactomes of ALS-related proteins.…”

Section: Discussionmentioning

confidence: 99%

“…GGGGCC repeat RNA-mediated RNA foci from C9orf72 mutations are predominantly associated with paraspeckle proteins SFPQ, NONO, RBM14, FUS, and HNRNPH in cells and brain tissue in FTD [ 150 ]. ALS-associated poly-GR and poly-PR DPR interact with paraspeckle components such as HNRNPF, RNRPH1, HNRNPM, SFPQ, NONO, FAM98, RBM14, and MATR3 as well as NEAT1 non-coding RNA [ 138 , 151 ]. Poly-PR DPR upregulates NEAT1 expression and suppresses the function of HNRNPF and HNRNPH1, leading to increased paraspeckle formation and neuronal toxicity [ 138 ].…”

Section: Rna-binding Proteins and Membrane-less Organellesmentioning

confidence: 99%

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RNA-Binding Proteins and the Complex Pathophysiology of ALS

Kim

Lee

2021

IJMS

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Genetic analyses of patients with amyotrophic lateral sclerosis (ALS) have identified disease-causing mutations and accelerated the unveiling of complex molecular pathogenic mechanisms, which may be important for understanding the disease and developing therapeutic strategies. Many disease-related genes encode RNA-binding proteins, and most of the disease-causing RNA or proteins encoded by these genes form aggregates and disrupt cellular function related to RNA metabolism. Disease-related RNA or proteins interact or sequester other RNA-binding proteins. Eventually, many disease-causing mutations lead to the dysregulation of nucleocytoplasmic shuttling, the dysfunction of stress granules, and the altered dynamic function of the nucleolus as well as other membrane-less organelles. As RNA-binding proteins are usually components of several RNA-binding protein complexes that have other roles, the dysregulation of RNA-binding proteins tends to cause diverse forms of cellular dysfunction. Therefore, understanding the role of RNA-binding proteins will help elucidate the complex pathophysiology of ALS. Here, we summarize the current knowledge regarding the function of disease-associated RNA-binding proteins and their role in the dysfunction of membrane-less organelles.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Rna-binding Proteins and Membrane-less Organellesmentioning

confidence: 99%

See 3 more Smart Citations

RNA-Binding Proteins and the Complex Pathophysiology of ALS

Kim

Lee

2021

IJMS

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Heterogeneous nuclear ribonucleoprotein A3 binds to the internal ribosomal entry site of enterovirus A71 and affects virus replication in neural cells

Lin,

Kuo

et al. 2024

J of Cellular Biochemistry

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Enterovirus A71 (EV‐A71) belongs to the genus Enterovirus of the Picornaviridae family and often causes outbreaks in Asia. EV‐A71 infection usually causes hand, foot, and mouth disease and can even affect the central nervous system, causing neurological complications or death. The 5′‐untranslated region (5′‐UTR) of EV‐A71 contains an internal ribosome entry site (IRES) that is responsible for the translation of viral proteins. IRES‐transacting factors can interact with the EV‐A71 5′‐UTR to regulate IRES activity. Heterogeneous nuclear ribonucleoprotein (hnRNP) A3 is a member of the hnRNP A/B protein family of RNA‐binding proteins and is involved in RNA transport and modification. We found that hnRNP A3 knockdown promoted the replication of EV‐A71 in neural calls. Conversely, increasing the expression of hnRNP A3 within cells inhibits the growth of EV‐A71. HnRNP A3 can bind to the EV‐A71 5′‐UTR, and knockdown of hnRNP A3 enhances the luciferase activity of the EV‐A71 5′‐UTR IRES. The localization of hnRNP A3 shifts from the nucleus to the cytoplasm of infected cells during viral infection. Additionally, EV‐A71 infection can increase the protein expression of hnRNP A3, and the protein level is correlated with efficient viral growth. Based on these findings, we concluded that hnRNP A3 plays a negative regulatory role in EV‐A71 replication within neural cells.

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Post‐translational modification sites are present in hydrophilic cavities of alpha‐synuclein, tau, FUS, and TDP‐43 fibrils: A molecular dynamics study

Kochen,

Seaney,

Vasandani

et al. 2024

Proteins

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Hydration plays a crucial role in the refolding of intrinsically disordered proteins into amyloid fibrils; however, the specific interactions between water and protein that may contribute to this process are still unknown. In our previous studies of alpha‐synuclein (aSyn), we have shown that waters confined in fibril cavities are stabilizing features of this pathological fold; and that amino acids that hydrogen bond with these confined waters modulate primary and seeded aggregation. Here, we extend our aSyn molecular dynamics (MD) simulations with three new polymorphs and correlate MD trajectory information with known post‐translational modifications (PTMs) and experimental data. We show that cavity residues are more evolutionarily conserved than non‐cavity residues and are enriched with PTM sites. As expected, the confinement within hydrophilic cavities results in more stably hydrated amino acids. Interestingly, cavity PTM sites display the longest protein‐water hydrogen bond lifetimes, three‐fold greater than non‐PTM cavity sites. Utilizing the deep mutational screen dataset by Newberry et al. and the Thioflavin T aggregation review by Pancoe et al. parsed using a fibril cavity/non‐cavity definition, we show that hydrophobic changes to amino acids in cavities have a larger effect on fitness and aggregation rate than residues outside cavities, supporting our hypothesis that these sites are involved in the inhibition of aSyn toxic fibrillization. Finally, we expand our study to include analysis of fibril structures of tau, FUS, TDP‐43, prion, and hnRNPA1; all of which contained hydrated cavities, with tau, FUS, and TDP‐43 recapitulating our PTM results in aSyn fibril cavities.

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The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis

Cited by 85 publications

References 220 publications

RNA-Binding Proteins and the Complex Pathophysiology of ALS

RNA-Binding Proteins and the Complex Pathophysiology of ALS

Heterogeneous nuclear ribonucleoprotein A3 binds to the internal ribosomal entry site of enterovirus A71 and affects virus replication in neural cells

Post‐translational modification sites are present in hydrophilic cavities of alpha‐synuclein, tau, FUS, and TDP‐43 fibrils: A molecular dynamics study

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