Role of selected mutations in the Q/N rich region of TDP-43 in EGFP-12xQ/N-induced aggregate formation

Budini, Mauricio; Romanò, Valentina; Avendaño‐Vázquez, S. Eréndira; Bembich, Sara; Buratti, Emanuele; Baralle, Francisco E.

doi:10.1016/j.brainres.2012.02.031

Cited by 41 publications

(30 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The entire C-terminal region of ∼160 amino acids is considered low complexity in that it is highly enriched in only four amino acids (glycine, glutamine, serine, and asparagine), which are similar to the residues enriched in yeast prion domains (March et al 2016). Some mutations are predicted to increase propensity for phosphorylation (Kabashi et al 2008) and spontaneous aggregation (Johnson et al 2009), while others are proposed to influence amyloid-like states that are available to TDP-43 via a short stretch of mostly Q/N (Fuentealba et al 2010;Budini et al 2012;Mompean et al 2016). These observations suggest that while changes in splicing and gene expression may be seen in disease, they are not due to differences in RNA recognition.…”

Section: Tdp-43mentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

View full text Add to dashboard Cite

Neurodegeneration is a leading cause of death in the developed world and a natural, albeit unfortunate, consequence of longer-lived populations. Despite great demand for therapeutic intervention, it is often the case that these diseases are insufficiently understood at the basic molecular level. What little is known has prompted much hopeful speculation about a generalized mechanistic thread that ties these disparate conditions together at the subcellular level and can be exploited for broad curative benefit. In this review, we discuss a prominent theory supported by genetic and pathological changes in an array of neurodegenerative diseases: that neurons are particularly vulnerable to disruption of RNA-binding protein dosage and dynamics. Here we synthesize the progress made at the clinical, genetic, and biophysical levels and conclude that this perspective offers the most parsimonious explanation for these mysterious diseases. Where appropriate, we highlight the reciprocal benefits of cross-disciplinary collaboration between disease specialists and RNA biologists as we envision a future in which neurodegeneration declines and our understanding of the broad importance of RNA processing deepens.

show abstract

Section: Tdp-43mentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

View full text Add to dashboard Cite

show abstract

“…Consequently, a number of studies have focused on the aggregation propensity of TDP-43 in the context of disease mutations (Budini et al, 2012; Jiang et al, 2013; Mompean et al, 2014), although the effects of TDP-43 aggregates on the severity of the disease phenotype in vivo are unclear(Ash et al, 2010; D'Alton et al, 2014; Estes et al, 2011). Here, we demonstrate here that the tested ALS-causing mutations result in perturbations to liquid phase separation via alteration of interactions of a uniquely well-conserved segment of the C-terminal domain.…”

Section: Discussionmentioning

confidence: 99%

ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain

et al. 2016

View full text Add to dashboard Cite

Summary RNA-binding protein TDP-43 mediates essential RNA processing but forms cytoplasmic neuronal inclusions via its C-terminal domain (CTD) in amyotrophic lateral sclerosis (ALS). It remains unclear if aggregated TDP-43 is neurotoxic and if ~50 ALS-associated missense mutations in TDP-43 CTD promote aggregation, or if loss-of-normal-function plays a role in disease. Recent work points to the ability of related proteins to assemble into functional phase-separated ribonucleoprotein granules via their structurally-disordered “prion-like” domains. Here, we provide atomic details on the structure and assembly of the low-complexity CTD of TDP-43 into liquid-liquid phase-separated in vitro granules and demonstrate that ALS-associated variants disrupt interactions within granules. Using NMR spectroscopy, simulation, and microscopy, we find that a subregion cooperatively but transiently folds into a helix that mediates TDP-43 phase separation. ALS-associated mutations disrupt phase separation by inhibiting interaction and helical stabilization. Therefore, ALS-associated mutations can disrupt TDP-43 interactions, affecting function beyond encouraging aggregation.

show abstract

“…In combination with the C terminus, intact or fragmented RRM2 was shown to severely enhance cellular aggregation and toxicity in cell models (12,13,15,38,57). The C terminus, which also contains a particularly aggregation-prone stretch (Met 311 -Met 323 ), was shown to have increased ␤-strand propensity and aggregation tendency (38), whereas a Gln/Asn-rich region that is critical for proper TDP-43 protein-protein interactions was also sufficient for aggregation of GFP fused with multiple Gln/Asn repeats (58). Taken together, these results suggest that the population of the RRM2 intermediate state could expose aggregation-prone residues, such as ␤3 and ␤5 (56), either through the intact domain, cleavage by caspases (13, 59 -61), or increased temperatures.…”

Section: Discussionmentioning

confidence: 99%