Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA

Woerner, Andreas C.; Frottin, Frédéric; Hornburg, Daniel; Feng, Linyin; Meissner, Felix; Patra, Maria; Tatzelt, Jörg; Mann, Matthias; Winklhofer, Konstanze F.; Hartl, F. Ulrich; Hipp, Mark S.

doi:10.1126/science.aad2033

Cited by 352 publications

(400 citation statements)

References 46 publications

Supporting

Mentioning

350

Contrasting

Unclassified

Order By: Relevance

“…Cytoplasmic protein aggregation affects nucleocytoplasmic import and export. 33 Therefore, it might be interesting to test whether TDP-43 mitochondrial accumulation also interferes with nuclear transport factors to regulate nucleocytoplasmic transport. Previously reported mutant TDP-43 animal models unanimously showed neuronal loss.…”

Section: Discussionmentioning

confidence: 99%

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization

et al. 2017

View full text Add to dashboard Cite

Dominant missense mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the cytoplasmic accumulation of TDP-43 represents a pathological hallmark in ALS and frontotemporal lobar degeneration (FTD). Behavioral investigation of the transgenic mouse model expressing the disease-causing human TDP-43 M337V mutant (TDP-43 M337V mice) is encumbered by premature death in homozygous transgenic mice and a reported lack of phenotype assessed by tail elevation and footprint in hemizygous transgenic mice. Here, using a battery of motor-coordinative and cognitive tests, we report robust motor-coordinative and cognitive deficits in hemizygous TDP-43 M337V mice by 8 months of age. After 12 months of age, cortical neurons are significantly affected by the mild expression of mutant TDP-43, characterized by cytoplasmic TDP-43 mislocalization, mitochondrial dysfunction, and neuronal loss. Compared with age-matched non-transgenic mice, TDP-43 M337V mice demonstrate a similar expression of total TDP-43 but higher levels of TDP-43 in mitochondria. Interestingly, a TDP-43 mitochondrial localization inhibitory peptide abolishes cytoplasmic TDP-43 accumulation, restores mitochondrial function, prevents neuronal loss, and alleviates motor-coordinative and cognitive deficits in adult hemizygous TDP-43 M337V mice. Thus, this study suggests hemizygous TDP-43 M337V mice as a useful animal model to study TDP-43 toxicity and further consolidates mitochondrial TDP-43 as a novel therapeutic target for TDP-43-linked neurodegenerative diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Several of these species are MGs. Off-pathway intermediate formation is also characteristic for the folding of CheY-like proteins, which share the flavodoxin-like fold (33,34). A MG that has been extensively studied is the off-pathway MG (MG off ) of the 179-residue flavodoxin from A. vinelandii (32, [35][36][37][38][39][40][41][42][43].…”

Section: W74mentioning

confidence: 99%

“…In contrast to native protein, this MG contains no β-sheet and is helical (Fig. 1B) (33,39,40). Under steady-state conditions the MG is in equilibrium with native apoflavodoxin.…”

Section: Introductionmentioning

confidence: 98%

“…The flavodoxin-like fold is an ancestral fold (30) and is archetypal for the class of αβα sandwiches. It has been well established that proteins with a flavodoxin-like architecture fold in vitro through involvement of an off-pathway intermediate (11,(31)(32)(33)(34)(35)(36)(37). Upon folding, the large majority of unfolded flavodoxin molecules temporarily misfold.…”

Section: Introductionmentioning

confidence: 99%

“…B, cartoon drawing of the four transiently structured regions of the off-pathway MG, which include α-helices (coloured blue) and structure that is neither α-helix nor β-strand (coloured orange) (33). These regions dock non-natively and form the core of apoflavodoxin's MG (33,35,39,40). The cartoon is a representation of structural elements in the MG, not of their packing.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The ribosome regulates flavodoxin folding

Houwman¹

View full text Add to dashboard Cite

TDP‐43 and FUS en route from the nucleus to the cytoplasm

Ederle¹,

2017

View full text Add to dashboard Cite

Misfolded or mislocalized RNA‐binding proteins (RBPs) and, consequently, altered mRNA processing, can cause neuronal dysfunction, eventually leading to neurodegeneration. Two prominent examples are the RBPs TAR DNA‐binding protein of 43 kDa (TDP‐43) and fused in sarcoma (FUS), which form pathological messenger ribonucleoprotein aggregates in patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative disorders. Here, we review the multiple functions of TDP‐43 and FUS in mRNA processing, both in the nucleus and in the cytoplasm. We discuss how TDP‐43 and FUS may exit the nucleus and how defects in both nuclear and cytosolic mRNA processing events, and possibly nuclear export defects, may contribute to neurodegeneration and ALS/FTD pathogenesis.

show abstract

Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA

Cited by 352 publications

References 46 publications

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization

The ribosome regulates flavodoxin folding

TDP‐43 and FUS en route from the nucleus to the cytoplasm

Contact Info

Product

Resources

About