Convergence of stress granules and protein aggregates in hippocampal cornu ammonis 1 at later reperfusion following global brain ischemia

DeGracia, Donald J.; Rudolph, Jennifer L.; Roberts, George G.; Rafols, José A.; Wang, Jie

doi:10.1016/j.neuroscience.2007.01.050

Cited by 35 publications

(47 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Currently, stress granules are known to contribute to the pathogenesis of several disorders, including fragile-X syndrome, spinal muscular atrophy, and ischemiareperfusion injury (5,25,28); like TDP-43 and FUS/TLS (fused in sarcoma/translated in liposarcoma) proteinopathies, these disorders are caused by altered RNA-binding proteins (4,5,24,25,28,54,75). In this study, we show that sorbitol is a novel stressor mediating TDP-43 and hnRNP A1 localization to TIAR ϩ and HuR ϩ stress granules; this was observed in both somatic (Hek293T cells) and nervous system (primary cultured glia) cell types.…”

Section: Discussionmentioning

confidence: 99%

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor

Dewey

Cenik

Sephton

et al. 2011

Molecular and Cellular Biology

302

306

View full text Add to dashboard Cite

TDP-43, or TAR DNA-binding protein 43, is a pathological marker of a spectrum of neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinpositive inclusions. TDP-43 is an RNA/DNA-binding protein implicated in transcriptional and posttranscriptional regulation. Recent work also suggests that TDP-43 associates with cytoplasmic stress granules, which are transient structures that form in response to stress. In this study, we establish sorbitol as a novel physiological stressor that directs TDP-43 to stress granules in Hek293T cells and primary cultured glia. We quantify the association of TDP-43 with stress granules over time and show that stress granule association and size are dependent on the glycine-rich region of TDP-43, which harbors the majority of pathogenic mutations. Moreover, we establish that cells harboring wild-type and mutant TDP-43 have distinct stress responses: mutant TDP-43 forms significantly larger stress granules, and is incorporated into stress granules earlier, than wild-type TDP-43; in striking contrast, wild-type TDP-43 forms more stress granules over time, but the granule size remains relatively unchanged. We propose that mutant TDP-43 alters stress granule dynamics, which may contribute to the progression of TDP-43 proteinopathies.TAR DNA-binding protein 43 (TDP-43) is a highly conserved, ubiquitously expressed RNA-binding protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) family (11,47,73). TDP-43 and other hnRNPs are multifunctional proteins that regulate gene expression in both the nucleus and the cytoplasm (47, 75). In the nucleus, TDP-43 binds singlestranded DNA and RNA (10,11,19,20,49,62) and can function as both a transcriptional repressor (1, 2, 62) and a splicing modulator (15,17,20,55). Specifically, TDP-43 regulates pre-mRNA splicing by binding mRNA with (UG) 6-12 sequences (19) and by recruiting other hnRNP proteins into repressive splicing complexes (10,18,55). However, as a nucleocytoplasmic shuttling protein (12), TDP-43 also has distinct cytoplasmic functions, including mRNA stabilization (74).Recent studies indicate that TDP-43 localizes to stress granules (SGs) in response to heat shock, oxidative stress, and chemical inducers of stress (23,33). SGs are dynamic cytoplasmic structures that are believed to act as sorting stations for mRNAs (5). SG composition and morphology differ according to stress and cell type (5, 39), but some core components are conserved. These core components include the RNA-binding protein TIAR (TIA-1 cytotoxic granule-associated RNA-binding protein-like 1) and the stalled translation initiation complex components eIF3 and eIF4G (44,45). In contrast, the incorporation of the RNA-binding proteins HuR and hnRNP A1 into SGs differs with the cell type and stress (5, 39). The physiological stressors that cause TDP-43 aggregates and SGs to form-and the cells in which this occurs-remain unresolved. Moreover, very little is known about the function of cytoplasmic TDP-43, a press...

show abstract

Section: Discussionmentioning

confidence: 99%

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor

Dewey

Cenik

Sephton

et al. 2011

Molecular and Cellular Biology

302

306

View full text Add to dashboard Cite

show abstract

“…In cultured cells, SG formation can be elicited with a variety of stress treatments, such as heat shock (42-44°C), osmotic shock, UV irradiation, or substances that elicit mitochondrial and/or oxidative stress (44). SG have also been observed in vivo (41,(45)(46)(47), and SG marker proteins were found to label the pathological FUS inclusions in post mortem brains of ALS/FTLD patients (33,42). Thus, it has been suggested that SG might be the precursors of the pathological FUS inclusions in ALS/FTLD-FUS patients (33).…”

mentioning

confidence: 99%

Requirements for Stress Granule Recruitment of Fused in Sarcoma (FUS) and TAR DNA-binding Protein of 43 kDa (TDP-43)

Bentmann

Neumann

Tahirović

et al. 2012

Journal of Biological Chemistry

250

288

View full text Add to dashboard Cite

“…One of the ways to avoid protein aggregation is keeping abnormal proteins soluble by molecular chaperone [26] . After lethal ischemia, misfolded or unfolded proteins were produced in the neurons and prone to aggregation [27] . Chaperones could combine with these abnormal proteins and prevent them from sticking together and accumulating in the cells [28] .…”

Section: Discussionmentioning

confidence: 99%

Ischemic preconditioning induces chaperone hsp70 expression and inhibits protein aggregation in the CA1 neurons of rats

Luo²,

Zhang³

et al. 2008

Neurosci. Bull.

View full text Add to dashboard Cite

Objective To investigate the effect of ischemic preconditioning on chaperone hsp70 expression and protein aggregation in the CA1 neurons of rats, and to further explore its potential neuroprotective mechanism. Methods Two-vesseloccluded transient global ischemia rat model was used. The rats were divided into sublethal 3-min ischemia group, lethal 10-min ischemia group and ischemic preconditioning group. Neuronal death in the CA1 region was observed by hematoxylineosin staining, and number of live neurons was assessed by cell counting under a light microscope. Immunochemistry and laser scanning confocal microscopy were used to observe the distribution of chaperone hsp70 in the CA1 neurons. Differential centrifuge was used to isolate cytosol, nucleus and protein aggregates fractions. Western blot was used to analyze the quantitative alterations of protein aggregates and inducible chaperone hsp70 in cellular fractions and in protein aggregates under different ischemic conditions. Results Histological examination showed that ischemic preconditioning significantly reduced delayed neuronal death in the hippocampus CA1 region (P < 0.01 vs 10-min ischemia group). Sublethal ischemic preconditioning induced chaperone hsp70 expression in the CA1 neurons after 24 h reperfusion following 10-min ischemia. Induced-hsp70 combined with the abnormal proteins produced during the secondary lethal 10-min ischemia and inhibited the formation of cytotoxic protein aggregates (P < 0.01 vs 10-min ischemia group). Conclusion Ischemic preconditioning induced chaperone hsp70 expression and inhibited protein aggregates formation in the CA1 neurons when suffered secondary lethal ischemia, which may protect neurons from death.

show abstract

Convergence of stress granules and protein aggregates in hippocampal cornu ammonis 1 at later reperfusion following global brain ischemia

Cited by 35 publications

References 30 publications

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor

TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor

Requirements for Stress Granule Recruitment of Fused in Sarcoma (FUS) and TAR DNA-binding Protein of 43 kDa (TDP-43)

Ischemic preconditioning induces chaperone hsp70 expression and inhibits protein aggregation in the CA1 neurons of rats

Contact Info

Product

Resources

About