Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation

Chang, Hsin-Li; Hou, Shin-Chen; Way, Tzong‐Der; Wong, Chi‐Huey; Wang, I-Fan

doi:10.1038/ncomms3757

Cited by 50 publications

(45 citation statements)

References 33 publications

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“…Intriguingly, Chd1 is linked to gene induction following stress [30, 32], and molecular chaperones are crucial in neurodegenerative processes [33–35]. TDP-43, like numerous other degenerative disease proteins, is aggregation-prone, and several heat shock proteins protect against its toxicity [36–40]. In accordance with these studies, we found that upregulation of Hsc4 and Hsp68 suppressed TDP-43 toxicity (Figure S2A, B).…”

Section: Resultssupporting

confidence: 82%

TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling

et al. 2017

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SUMMARY Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43 mediated impairments are conserved in mammalian cells, and importantly the human orthologue CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to ALS/FTD.

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Section: Resultssupporting

confidence: 82%

TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling

et al. 2017

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“…To this end, we treated HeLa cells with various compounds described in the literature that were shown to induce pathological changes in TDP-43, though not necessarily TDP-43 truncation. We tested the proteasome inhibitor MG132 (10 μM, 4 h) [13, 42], the oxidative stressors hydrogen peroxide (1 mM, 60 min) [43] and sodium arsenite (0.5 mM, 30 min) [44], the sarco-endoplasmic reticulum Ca 2+ -ATPase inhibitor thapsigargin (1 μM, 60 min) [15, 29] and the oxidative and osmotic stressor D-sorbitol (0.4 M, 60 min) [14]. However, while MG132 as well as thapsigargin and D-sorbitol have been described to promote cleavage of TDP-43, we observed a reduction of full-length TDP-43 as well as the formation of a 35 kDa fragment (CTF35) with D-sorbitol only (Fig 2) [14, 29, 42].…”

Section: Resultsmentioning

confidence: 99%

Truncation of the TAR DNA-binding protein 43 is not a prerequisite for cytoplasmic relocalization, and is suppressed by caspase inhibition and by introduction of the A90V sequence variant

et al. 2017

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The RNA-binding and -processing protein TAR DNA-binding protein 43 (TDP-43) is heavily linked to the underlying causes and pathology of neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In these diseases, TDP-43 is mislocalized, hyperphosphorylated, ubiquitinated, aggregated and cleaved. The importance of TDP-43 cleavage in the disease pathogenesis is still poorly understood. Here we detail the use of D-sorbitol as an exogenous stressor that causes TDP-43 cleavage in HeLa cells, resulting in a 35 kDa truncated product that accumulates in the cytoplasm within one hour of treatment. We confirm that the formation of this 35 kDa cleavage product is mediated by the activation of caspases. Inhibition of caspases blocks the cleavage of TDP-43, but does not prevent the accumulation of full-length protein in the cytoplasm. Using D-sorbitol as a stressor and caspase activator, we also demonstrate that the A90V variant of TDP-43, which lies adjacent to the caspase cleavage site within the nuclear localization sequence of TDP-43, confers partial resistance against caspase-mediated generation of the 35 kDa cleavage product.

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“…Heat‐shock protein defects have been implicated in PD (Yang et al ., 2015) and AD (Ou et al ., 2014), and HspB1 mutations are associated with familial motor neuron diseases (Muranova et al ., 2015). Hsp90 and its co‐chaperones regulate tau and Aβ processing (Blair et al ., 2014), and Hsp90 may specifically protect TDP‐43 from ROS‐induced aggregation (Chang et al ., 2013a). The mitochondrial HSP70, also called ‘stress‐70’ or ‘mortalin’, is implicated in PD and in vitro longevity (Wadhwa et al ., 2015).…”

Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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SummaryNeurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

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Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation

Cited by 50 publications

References 33 publications

TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling

TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling

Truncation of the TAR DNA-binding protein 43 is not a prerequisite for cytoplasmic relocalization, and is suppressed by caspase inhibition and by introduction of the A90V sequence variant

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

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