T‐complex protein 1‐ring complex enhances retrograde axonal transport by modulating tau phosphorylation

Chen, Xu-Qiao; Fang, Fang; Florio, Jazmin; Rockenstein, Edward; Masliah, Eliezer; Mobley, William C.; Rissman, Robert A.; Wu, Chengbiao

doi:10.1111/tra.12610

Cited by 25 publications

(21 citation statements)

References 91 publications

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“…The over expression of CCT5(ε) was also shown to increase the retrograde transport of BDNF in wild type neurons (Chen et al, 2018). Interestingly, tau protein was required for this effect and CCT5(ε) appeared to be connected to increased CDK5 activity and subsequent tau phosphorylation/effects on microtubule bundling (Chen et al, 2018). Therefore several CCT subunits, when in their monomeric forms, appear to have the potential to influence axonal transport, revealing a further level of complexity of the functions of the CCT molecular chaperone.…”

Section: Cct and Axonal Transportmentioning

confidence: 97%

Section: Cct and Axonal Transportmentioning

confidence: 99%

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The Molecular Chaperone CCT/TRiC: An Essential Component of Proteostasis and a Potential Modulator of Protein Aggregation

Grantham

2020

Front. Genet.

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Chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC) is an essential eukaryotic molecular chaperone. It is a multi-subunit oligomer of two rings of eight individual protein subunits. When assembled, each of the eight CCT subunits occupies a specific position within each chaperonin ring. Thus a geometrically defined binding interface is formed from the divergent sequences within the CCT subunit substrate binding domains. CCT is required for the folding of the abundant cytoskeletal proteins actin and tubulin, which in turn form assemblies of microfilaments and microtubules. CCT is also involved in the folding of some additional protein substrates and some CCT subunits have been shown to have functions when monomeric. Since observations were made in worms over a decade ago using an RNAi screen, which connected CCT subunits to the aggregation of polyglutamine tracts, a role for CCT as a potential modulator of protein aggregation has started to emerge. Here there will be a focus on how mechanistically CCT may be able to achieve this and if this potential function of CCT provides any insights and directions for developing future treatments for protein aggregation driven neurodegenerative diseases generally, many of which are associated with aging.

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Section: Cct and Axonal Transportmentioning

confidence: 97%

Section: Cct and Axonal Transportmentioning

confidence: 99%

The Molecular Chaperone CCT/TRiC: An Essential Component of Proteostasis and a Potential Modulator of Protein Aggregation

Grantham

2020

Front. Genet.

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“…To determine if Posiphen treatment impacted neurotrophin signaling and trafficking we examined the retrograde transport of BDNF in primary cultures of E18 Ts65Dn or 2N cortical neurons maintained in microfluidic culture chambers (Figure 2A, B) in which axons are separated from their corresponding cell bodies 71 . Quantum dot–labeled BDNF (QD‐BDNF) was used to track axonal transport of BDNF by live cell imaging 72 (Figure 2B). Compared with 2N neurons, Ts65Dn neurons displayed slower instantaneous (ie, moving) velocity and an increase in endosome pausing (Figure 2C‐E).…”

Section: New or Updated Hypothesismentioning

confidence: 99%

Targeting increased levels of APP in Down syndrome: Posiphen‐mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model

Chen

Salehi

Pearn

et al. 2020

Alzheimer's & Dementia

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Objective Recent clinical trials targeting amyloid beta (Aβ) and tau in Alzheimer's disease (AD) have yet to demonstrate efficacy. Reviewing the hypotheses for AD pathogenesis and defining possible links between them may enhance insights into both upstream initiating events and downstream mechanisms, thereby promoting discovery of novel treatments. Evidence that in Down syndrome (DS), a population markedly predisposed to develop early onset AD, increased APP gene dose is necessary for both AD neuropathology and dementia points to normalization of the levels of the amyloid precursor protein (APP) and its products as a route to further define AD pathogenesis and discovering novel treatments. Background AD and DS share several characteristic manifestations. DS is caused by trisomy of whole or part of chromosome 21; this chromosome contains about 233 protein‐coding genes, including APP. Recent evidence points to a defining role for increased expression of the gene for APP and for its 99 amino acid C‐terminal fragment (C99, also known as β‐CTF) in dysregulating the endosomal/lysosomal system. The latter is critical for normal cellular function and in neurons for transmitting neurotrophic signals. New/updated hypothesis We hypothesize that the increase in APP gene dose in DS initiates a process in which increased levels of full‐length APP (fl‐APP) and its products, including β‐CTF and possibly Aβ peptides (Aβ42 and Aβ40), drive AD pathogenesis through an endosome‐dependent mechanism(s), which compromises transport of neurotrophic signals. To test this hypothesis, we carried out studies in the Ts65Dn mouse model of DS and examined the effects of Posiphen, an orally available small molecule shown in prior studies to reduce fl‐APP. In vitro, Posiphen lowered fl‐APP and its C‐terminal fragments, reversed Rab5 hyperactivation and early endosome enlargement, and restored retrograde transport of neurotrophin signaling. In vivo, Posiphen treatment (50 mg/kg/d, 26 days, intraperitoneal [i.p.]) of Ts65Dn mice was well tolerated and demonstrated no adverse effects in behavior. Treatment resulted in normalization of the levels of fl‐APP, C‐terminal fragments and small reductions in Aβ species, restoration to normal levels of Rab5 activity, reduced phosphorylated tau (p‐tau), and reversed deficits in TrkB (tropomyosin receptor kinase B) activation and in the Akt (protein kinase B [PKB]), ERK (extracellular signal‐regulated kinase), and CREB (cAMP response element–binding protein) signaling pathways. Remarkably, Posiphen treatment also restored the level of choline acetyltransferase protein to 2N levels. These findings support the APP gene dose hypothesis, point to the need for additional studies to explore the mechanisms by which increased APP gene expression acts to increase the risk for AD in DS, and to possible utility of treatments to normalize the levels of APP and its products for preventing AD in those with DS. Major challenges for the hypothesis Important unanswered questions are: (1) When should one intervene in t...

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“…TCP-1 forms a complex called tailless complex polypeptide 1 ring complex (TRiC) or chaperonin-containing TCP-1 (CCT), which acts as a chaperon for tubulin and actin 34 . In addition to being a chaperon, TRiC enhances retrograde axonal transport in neurons 35 , forms a complex with BBS6, BBS10, and BBS12, and mediates BBSome assembly 36 . BBSome is a complex of seven BBS proteins (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, and BBS9) and is involved in the recognition and trafficking of cargo in or to cilia and flagella.…”

Section: Dlec1 Is Indispensable For Spermatogenesis and Male Fertilitmentioning

confidence: 99%

Dlec1 is required for spermatogenesis and male fertility in mice

Okitsu

Nagano

Yamagata

et al. 2020

Sci Rep

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Deleted in lung and esophageal cancer 1 (DLEC1) is a tumour suppressor gene that is downregulated in various cancers in humans; however, the physiological and molecular functions of DLEC1 are still unclear. This study investigated the critical role of Dlec1 in spermatogenesis and male fertility in mice. Dlec1 was significantly expressed in testes, with dominant expression in germ cells. We disrupted Dlec1 in mice and analysed its function in spermatogenesis and male fertility. Dlec1 deletion caused male infertility due to impaired spermatogenesis. Spermatogenesis progressed normally to step 8 spermatids in Dlec1−/− mice, but in elongating spermatids, we observed head deformation, a shortened tail, and abnormal manchette organization. These phenotypes were similar to those of various intraflagellar transport (IFT)-associated gene-deficient sperm. In addition, DLEC1 interacted with tailless complex polypeptide 1 ring complex (TRiC) and Bardet–Biedl Syndrome (BBS) protein complex subunits, as well as α- and β-tubulin. DLEC1 expression also enhanced primary cilia formation and cilia length in A549 lung adenocarcinoma cells. These findings suggest that DLEC1 is a possible regulator of IFT and plays an essential role in sperm head and tail formation in mice.

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T‐complex protein 1‐ring complex enhances retrograde axonal transport by modulating tau phosphorylation

Cited by 25 publications

References 91 publications

The Molecular Chaperone CCT/TRiC: An Essential Component of Proteostasis and a Potential Modulator of Protein Aggregation

The Molecular Chaperone CCT/TRiC: An Essential Component of Proteostasis and a Potential Modulator of Protein Aggregation

Targeting increased levels of APP in Down syndrome: Posiphen‐mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model

Dlec1 is required for spermatogenesis and male fertility in mice

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