Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers

Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder affecting carriers of premutation alleles (PM) of the X-linked FMR1 gene, which contain CGG repeat expansions of 55–200 range in a non-coding region. This late-onset disorder is characterised by the presence of tremo...

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Autores principales:	Danuta Z. Loesch, Bruce E. Kemp, Minh Q. Bui, Paul R. Fisher, Claire Y. Allan, Oana Sanislav, Kevin R. W. Ngoei, Anna Atkinson, Flora Tassone, Sarah J. Annesley, Elsdon Storey
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	FMR1 premutation Fragile X-associated tremor/ataxia syndrome (FXTAS) motor scores SCL-90 scale lymphoblasts' bioenergetics measures AMPK Psychiatry RC435-571
Acceso en línea:	https://doaj.org/article/ae4074102c024825816d2c1abaa6b6b0
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spelling	oai:doaj.org-article:ae4074102c024825816d2c1abaa6b6b02021-11-22T04:52:04ZCellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers1664-064010.3389/fpsyt.2021.747268https://doaj.org/article/ae4074102c024825816d2c1abaa6b6b02021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fpsyt.2021.747268/fullhttps://doaj.org/toc/1664-0640Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder affecting carriers of premutation alleles (PM) of the X-linked FMR1 gene, which contain CGG repeat expansions of 55–200 range in a non-coding region. This late-onset disorder is characterised by the presence of tremor/ataxia and cognitive decline, associated with the white matter lesions throughout the brain, especially involving the middle cerebellar peduncles. Nearly half of older male and ~ 20% of female PM carriers develop FXTAS. While there is evidence for mitochondrial dysfunction in neural and some peripheral tissues from FXTAS patients (though less obvious in the non-FXTAS PM carriers), the results from peripheral blood mononuclear cells (PBMC) are still controversial. Motor, cognitive, and neuropsychiatric impairments were correlated with measures of mitochondrial and non-mitochondrial respiratory activity, AMPK, and TORC1 cellular stress-sensing protein kinases, and CGG repeat size, in a sample of adult FXTAS male and female carriers. Moreover, the levels of these cellular measures, all derived from Epstein- Barr virus (EBV)- transformed and easily accessible blood lymphoblasts, were compared between the FXTAS (N = 23) and non-FXTAS (n = 30) subgroups, and with baseline data from 33 healthy non-carriers. A significant hyperactivity of cellular bioenergetics components as compared with the baseline data, more marked in the non-FXTAS PMs, was negatively correlated with repeat numbers at the lower end of the CGG-PM distribution. Significant associations of these components with motor impairment measures, including tremor-ataxia and parkinsonism, and neuropsychiatric changes, were prevalent in the FXTAS subgroup. Moreover, a striking elevation of AMPK activity, and a decrease in TORC1 levels, especially in the non-FXTAS carriers, were related to the size of CGG expansion. The bioenergetics changes in blood lymphoblasts are biomarkers of the clinical status of FMR1 carriers. The relationship between these changes and neurological involvement in the affected carriers suggests that brain bioenergetic alterations are reflected in this peripheral tissue. A possible neuroprotective role of stress sensing kinase, AMPK, in PM carriers, should be addressed in future longitudinal studies. A decreased level of TORC1—the mechanistic target of the rapamycin complex, suggests a possible future approach to therapy in FXTAS.Danuta Z. LoeschBruce E. KempBruce E. KempMinh Q. BuiPaul R. FisherClaire Y. AllanOana SanislavKevin R. W. NgoeiAnna AtkinsonFlora TassoneFlora TassoneSarah J. AnnesleyElsdon StoreyFrontiers Media S.A.articleFMR1 premutationFragile X-associated tremor/ataxia syndrome (FXTAS)motor scoresSCL-90 scalelymphoblasts' bioenergetics measuresAMPKPsychiatryRC435-571ENFrontiers in Psychiatry, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	FMR1 premutation Fragile X-associated tremor/ataxia syndrome (FXTAS) motor scores SCL-90 scale lymphoblasts' bioenergetics measures AMPK Psychiatry RC435-571
spellingShingle	FMR1 premutation Fragile X-associated tremor/ataxia syndrome (FXTAS) motor scores SCL-90 scale lymphoblasts' bioenergetics measures AMPK Psychiatry RC435-571 Danuta Z. Loesch Bruce E. Kemp Bruce E. Kemp Minh Q. Bui Paul R. Fisher Claire Y. Allan Oana Sanislav Kevin R. W. Ngoei Anna Atkinson Flora Tassone Flora Tassone Sarah J. Annesley Elsdon Storey Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers
description	Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder affecting carriers of premutation alleles (PM) of the X-linked FMR1 gene, which contain CGG repeat expansions of 55–200 range in a non-coding region. This late-onset disorder is characterised by the presence of tremor/ataxia and cognitive decline, associated with the white matter lesions throughout the brain, especially involving the middle cerebellar peduncles. Nearly half of older male and ~ 20% of female PM carriers develop FXTAS. While there is evidence for mitochondrial dysfunction in neural and some peripheral tissues from FXTAS patients (though less obvious in the non-FXTAS PM carriers), the results from peripheral blood mononuclear cells (PBMC) are still controversial. Motor, cognitive, and neuropsychiatric impairments were correlated with measures of mitochondrial and non-mitochondrial respiratory activity, AMPK, and TORC1 cellular stress-sensing protein kinases, and CGG repeat size, in a sample of adult FXTAS male and female carriers. Moreover, the levels of these cellular measures, all derived from Epstein- Barr virus (EBV)- transformed and easily accessible blood lymphoblasts, were compared between the FXTAS (N = 23) and non-FXTAS (n = 30) subgroups, and with baseline data from 33 healthy non-carriers. A significant hyperactivity of cellular bioenergetics components as compared with the baseline data, more marked in the non-FXTAS PMs, was negatively correlated with repeat numbers at the lower end of the CGG-PM distribution. Significant associations of these components with motor impairment measures, including tremor-ataxia and parkinsonism, and neuropsychiatric changes, were prevalent in the FXTAS subgroup. Moreover, a striking elevation of AMPK activity, and a decrease in TORC1 levels, especially in the non-FXTAS carriers, were related to the size of CGG expansion. The bioenergetics changes in blood lymphoblasts are biomarkers of the clinical status of FMR1 carriers. The relationship between these changes and neurological involvement in the affected carriers suggests that brain bioenergetic alterations are reflected in this peripheral tissue. A possible neuroprotective role of stress sensing kinase, AMPK, in PM carriers, should be addressed in future longitudinal studies. A decreased level of TORC1—the mechanistic target of the rapamycin complex, suggests a possible future approach to therapy in FXTAS.
format	article
author	Danuta Z. Loesch Bruce E. Kemp Bruce E. Kemp Minh Q. Bui Paul R. Fisher Claire Y. Allan Oana Sanislav Kevin R. W. Ngoei Anna Atkinson Flora Tassone Flora Tassone Sarah J. Annesley Elsdon Storey
author_facet	Danuta Z. Loesch Bruce E. Kemp Bruce E. Kemp Minh Q. Bui Paul R. Fisher Claire Y. Allan Oana Sanislav Kevin R. W. Ngoei Anna Atkinson Flora Tassone Flora Tassone Sarah J. Annesley Elsdon Storey
author_sort	Danuta Z. Loesch
title	Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers
title_short	Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers
title_full	Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers
title_fullStr	Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers
title_full_unstemmed	Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers
title_sort	cellular bioenergetics and ampk and torc1 signalling in blood lymphoblasts are biomarkers of clinical status in fmr1 premutation carriers
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/ae4074102c024825816d2c1abaa6b6b0
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Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers

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