CCT complex restricts neuropathogenic protein aggregation via autophagy

Pavel, Mariana; Imarisio, Sara; Menzies, Fiona M.; Jimenez-Sanchez, Maria; Siddiqi, Farah H.; Wu, Xiaoting; Renna, Maurizio; O’Kane, Cahir J.; Crowther, Damian C.; Rubinsztein, David C.

doi:10.1038/ncomms13821

Cited by 115 publications

(111 citation statements)

References 72 publications

(127 reference statements)

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“…Autophagosomes (yellow) and autolysosomes (red) in primary neurons. The different images show primary neurons from a transgenic mouse model expressing monomeric red fluorescent protein (mRFP)–green fluorescent protein (GFP)–light chain 3 (LC3) . This model allows one to distinguish non‐acidified autophagosomes (red and green=yellow) from acidified autolysosomes (red only), as the GFP fluorescence is more rapidly quenched by the low lysosomal pH.…”

Section: List Of Genes and Diseases Associated With Impaired Autophagmentioning

confidence: 99%

“…The CCT complex prevents accumulation of various autophagy substrates primarily by mediating autophagy rather than through its direct chaperone activity preventing aggregation of such proteins. CCT5 promotes autophagosome degradation by regulating lysosome function, as it has been shown that CCT5 disruption reduced the trafficking of lysosomal enzymes and the v‐ATPase to lysosomes, possibly via interactions with cytoskeleton proteins …”

Section: Hereditary Spastic Paraplegiamentioning

confidence: 99%

“…CCT5 promotes autophagosome degradation by regulating lysosome function, as it has been shown that CCT5 disruption reduced the trafficking of lysosomal enzymes and the v-ATPase to lysosomes, possibly via interactions with cytoskeleton proteins. 17…”

Section: Hereditary Spastic Paraplegiamentioning

confidence: 99%

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Autophagy in childhood neurological disorders

Zhu¹,

Runwal²,

Obrocki³

et al. 2018

Develop Med Child Neuro

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Autophagy is a tightly modulated lysosomal degradation pathway. Genetic disorders of autophagy during nervous system development may lead to developmental delay, neurodegeneration, and other neurological signs in children. Here we aimed to summarize single gene disorders that perturb various steps of autophagy pathway and their roles in the causation of childhood neurological diseases. Numerous childhood‐onset disorders are caused by mutations that impact the autophagy pathway. These can manifest with a range of features including ataxia, spastic paraplegia, and intellectual disability. Defective proteins causing such diseases can interfere with autophagy flux at different stages of the itinerary. Defective autophagy may be an important contributor to the pathological features of various childhood neurodegenerative diseases and lead to the accumulation of aberrant protein and dysfunctional organelles. Insights into the relevant cell biological processes may help understand pathophysiological mechanisms and inspire autophagy‐restoring therapeutic approaches. What this paper adds Numerous childhood‐onset disorders are caused by mutations that impact the autophagy pathway. Defective autophagy is a feature of some mutations that cause ataxia, spastic paraplegia, and intellectual disability.

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Section: List Of Genes and Diseases Associated With Impaired Autophagmentioning

confidence: 99%

Section: Hereditary Spastic Paraplegiamentioning

confidence: 99%

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Autophagy in childhood neurological disorders

Zhu¹,

Runwal²,

Obrocki³

et al. 2018

Develop Med Child Neuro

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“…Further CCT5 expression was found to be also decreased in Alzheimer’s disease (85). It is thus important to understand how decreased activity of CCT complex or individual CCT subunit impacts the stabilization and turnover of tau, whose pathogenic species also accumulates in Alzheimer’s disease.…”

Section: Discussionmentioning

confidence: 99%

“…84 Further CCT5 expression was found to be also decreased in Alzheimer's disease. 85 It is thus important to understand how decreased activity of CCT complex or individual CCT subunit impacts the stabilization and turnover of tau, whose pathogenic species also accumulates in AD. Although the physiological implications remain to be defined, our study has established that increased expression of CCT5 had a clear impact on tau-mediated functions such as axonal transport.…”

Section: Discussionmentioning

confidence: 99%

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

Chen

Fang

Florio

et al. 2018

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The cytosolic chaperonin T-complex protein (TCP) 1-ring complex (TRiC) has been shown to exert neuroprotective effects on axonal transport through clearance of mutant Huntingtin (mHTT) in Huntington's disease. However, it is presently unknown if TRiC also has any effect on axonal transport in wild-type neurons. Here, we examined how TRiC impacted the retrograde axonal transport of brain-derived neurotrophic factor (BDNF). We found that expression of a single TRiC subunit significantly enhanced axonal transport of BDNF, leading to an increase in instantaneous velocity with a concomitant decrease in pauses for retrograde BDNF transport. The transport enhancing effect by TRiC was dependent on endogenous tau expression because no effect was seen in neurons from tau knockout mice. We showed that TRiC regulated the level of cyclin-dependent kinase 5 (CDK5)/p35 positively, contributing to TRiC-mediated tau phosphorylation (ptau). Expression of a single TRiC subunit increased the level of ptau while downregulation of the TRiC complex decreased ptau. We further demonstrated that TRiC-mediated increase in ptau induced detachment of tau from microtubules. Our study has thus revealed that TRiC-mediated increase in tau phosphorylation impacts retrograde axonal transport.

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Revisiting the chaperonin T‐complex protein‐1 ring complex in human health and disease: A proteostasis modulator and beyond

Zeng,

Han,

Pan

et al. 2024

Clinical & Translational Med

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BackgroundDisrupted protein homeostasis (proteostasis) has been demonstrated to facilitate the progression of various diseases. The cytosolic T‐complex protein‐1 ring complex (TRiC/CCT) was discovered to be a critical player in orchestrating proteostasis by folding eukaryotic proteins, guiding intracellular localisation and suppressing protein aggregation. Intensive investigations of TRiC/CCT in different fields have improved the understanding of its role and molecular mechanism in multiple physiological and pathological processes.Main bodyIn this review, we embark on a journey through the dynamic protein folding cycle of TRiC/CCT, unraveling the intricate mechanisms of its substrate selection, recognition, and intriguing folding and assembly processes. In addition to discussing the critical role of TRiC/CCT in maintaining proteostasis, we detail its involvement in cell cycle regulation, apoptosis, autophagy, metabolic control, adaptive immunity and signal transduction processes. Furthermore, we meticulously catalogue a compendium of TRiC‐associated diseases, such as neuropathies, cardiovascular diseases and various malignancies. Specifically, we report the roles and molecular mechanisms of TRiC/CCT in regulating cancer formation and progression. Finally, we discuss unresolved issues in TRiC/CCT research, highlighting the efforts required for translation to clinical applications, such as diagnosis and treatment.ConclusionThis review aims to provide a comprehensive view of TRiC/CCT for researchers to inspire further investigations and explorations of potential translational possibilities.

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CCT complex restricts neuropathogenic protein aggregation via autophagy

Cited by 115 publications

References 72 publications

Autophagy in childhood neurological disorders

Autophagy in childhood neurological disorders

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

Revisiting the chaperonin T‐complex protein‐1 ring complex in human health and disease: A proteostasis modulator and beyond

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