A human CCT5 gene mutation causing distal neuropathy impairs hexadecamer assembly in an archaeal model

Min, Won‐Ki; Angileri, Francesca; Luo, Haibin; Lauria, Antonino; Shanmugasundaram, Maruda; Almerico, Anna Maria; Cappello, Francesco; Macario, Everly Conway de; Lednev, Igor K.; Macario, Alberto J. L.; Robb, Frank T.

doi:10.1038/srep06688

Cited by 20 publications

(38 citation statements)

References 39 publications

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“…Here, one key player is chaperonin containing TCP-1 (CCT, also known as TRiC or group II chaperonin), a cytosolic ATP-dependent eukaryotic chaperonin comprising two rings of eight different but related subunits, each thought to be represented once per eight-membered ring. Autosomal recessive mutations of the CCT5 and CCT4 subunits lead to loss-of function phenotypes that manifest with a devastating sensory neuropathy45. Moreover, recent studies suggested that mRNA levels of the TRiC complex are repressed in Alzheimer's disease patient brain samples6.…”

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confidence: 99%

CCT complex restricts neuropathogenic protein aggregation via autophagy

et al. 2016

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Aberrant protein aggregation is controlled by various chaperones, including CCT (chaperonin containing TCP-1)/TCP-1/TRiC. Mutated CCT4/5 subunits cause sensory neuropathy and CCT5 expression is decreased in Alzheimer's disease. Here, we show that CCT integrity is essential for autophagosome degradation in cells or Drosophila and this phenomenon is orchestrated by the actin cytoskeleton. When autophagic flux is reduced by compromise of individual CCT subunits, various disease-relevant autophagy substrates accumulate and aggregate. The aggregation of proteins like mutant huntingtin, ATXN3 or p62 after CCT2/5/7 depletion is predominantly autophagy dependent, and does not further increase with CCT knockdown in autophagy-defective cells/organisms, implying surprisingly that the effect of loss-of-CCT activity on mutant ATXN3 or huntingtin oligomerization/aggregation is primarily a consequence of autophagy inhibition rather than loss of physiological anti-aggregation activity for these proteins. Thus, our findings reveal an essential partnership between two key components of the proteostasis network and implicate autophagy defects in diseases with compromised CCT complex activity.

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CCT complex restricts neuropathogenic protein aggregation via autophagy

et al. 2016

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“…Archaea have not been used as models to specifically study molecular aspects of human chaperonopathies until very recently (Min et al, 2014). However, studies on the structure and properties of the thermosome, the archaeal equivalent of the human CCT, have been going on for nearly 30 years.…”

Section: An Archaeal Experimental Modelmentioning

confidence: 99%

“…In the wild type CCT5 the amino acid His is at this position but in the pathogenic mutant His is replaced by Arg. We found by a series of alignments and 3D modeling studies that position 138 in Pf-Cpn is equivalent to the 147 position in human CCT5 and it is occupied by Ile (Figure 5; information on the primary and secondary structures is available in Min et al, 2014). To examine the impact of the mutations we used Pf-CD1, which is the recombinant molecule Pf-Cpn lacking the last 22 amino acids that are involved in extreme heat resistance and have no match in the human CCTs.…”

Section: The Thermosome Of Pyrococcus Furiosusmentioning

confidence: 99%

“…AMP-PNP (β,γ-Imidoadenosine 5′-triphosphate lithium salt hydrate; green stick) and magnesium ion (yellow ball). Source: Min et al, 2014.…”

Section: The Thermosome Of Pyrococcus Furiosusmentioning

confidence: 99%

“…In conclusion, the Arg mutation affects the formation and stability of functional hexadecamers. Indeed, in native PAGE, Pf-R appears predominantly as oligomers smaller than hexadecamers and as monomers in contrast to Pf-CD1 and Pf-H (Min et al, 2014). …”

Section: The Thermosome Of Pyrococcus Furiosusmentioning

confidence: 99%

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Prokaryotic Chaperonins as Experimental Models for Elucidating Structure-Function Abnormalities of Human Pathogenic Mutant Counterparts

Macario

Robb

Macario

2017

Front. Mol. Biosci.

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All archaea have a chaperonin of Group II (thermosome) in their cytoplasm and some have also a chaperonin of Group I (GroEL; Cpn60; Hsp60). Conversely, all bacteria have GroEL, some in various copies, but only a few have, in addition, a chaperonin (tentatively designated Group III chaperonin) very similar to that occurring in all archaea, i.e., the thermosome subunit, and in the cytosol of eukaryotic cells, named CCT. Thus, nature offers a range of prokaryotic organisms that are potentially useful as experimental models to study the human CCT and its abnormalities. This is important because many diseases, the chaperonopathies, have been identified in which abnormal chaperones, including mutant CCT, are determinant etiologic-pathogenic factors and, therefore, research is needed to elucidate their pathologic features at the molecular level. Such research should lead to the clarification of the molecular mechanisms underlying the pathologic lesions observed in the tissues and organs of patients with chaperonopathies. Information on these key issues is necessary to make progress in diagnosis and treatment. Some of the archaeal organisms as well as some of the bacterial models suitable for studying molecular aspects pertinent to human mutant chaperones are discussed here, focusing on CCT. Results obtained with the archaeon Pyrococcus furiosus model to investigate the impact of a pathogenic CCT5 mutation on molecular properties and chaperoning functions are reviewed. The pathogenic mutation examined weakens the ability of the chaperonin subunit to form stable hexadecamers and as a consequence, the chaperoning functions of the complex are impaired. The future prospect is to find means for stabilizing the hexadecamer, which should lead to a recovering of chaperone function and the improving of lesions and clinical condition.

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Zebrafish as a Model for the Study of Chaperonopathies

Bellipanni

Cappello

Scalia

et al. 2016

Journal Cellular Physiology

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There is considerable information on the clinical manifestations and mode of inheritance for many genetic chaperonopathies but little is known on the molecular mechanisms underlying the cell and tissue abnormalities that characterize them. This scarcity of knowledge is mostly due to the lack of appropriate animal models that mimic closely the human molecular, cellular, and histological characteristics. In this article we introduce zebrafish as a suitable model to study molecular and cellular mechanisms pertaining to human chaperonopathies. Genetic chaperonopathies manifest themselves from very early in life so it is necessary to examine the impact of mutant chaperone genes during development, starting with fertilization and proceeding throughout the entire ontogenetic process. Zebrafish is amenable to such developmental analysis as well as studies during adulthood. In addition, the zebrafish genome contains a wide range of genes encoding proteins similar to those that form the chaperoning system of humans. This, together with the availability of techniques for genetic manipulations and for examination of all stages of development, makes zebrafish the organism of choice for the analysis of the molecular features and pathogenic mechanisms pertaining to human chaperonopathies.

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A human CCT5 gene mutation causing distal neuropathy impairs hexadecamer assembly in an archaeal model

Cited by 20 publications

References 39 publications

CCT complex restricts neuropathogenic protein aggregation via autophagy

CCT complex restricts neuropathogenic protein aggregation via autophagy

Prokaryotic Chaperonins as Experimental Models for Elucidating Structure-Function Abnormalities of Human Pathogenic Mutant Counterparts

Zebrafish as a Model for the Study of Chaperonopathies

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