Telomere length analysis on leukocytes derived from patients with Huntington Disease

PerezGrovas‐Saltijeral, Adriana; Ochoa, Adriana; Miranda‐Duarte, Antonio; Martínez-Ruano, Leticia; Jara‐Prado, Aurelio; Camacho‐Molina, Alejandra; Hidalgo‐Bravo, Alberto

doi:10.1016/j.mad.2019.111189

Cited by 13 publications

(14 citation statements)

References 36 publications

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“…Interestingly, 3 h pre-treatment with rapamycin reduced cisplatin-induced neuronal apoptosis, as revealed by the decrease in caspase-3 activity 24 h post-treatment. In addition to apoptosis, several reports have suggested a role for cellular senescence in the pathogenesis of neurodegeneration ( Bhat et al, 2012 ; Birger et al, 2019 ; Nicaise et al, 2019 ; PerezGrovas-Saltijeral et al, 2020 ). Thus, the expression of further markers of apoptosis and senescence were assessed.…”

Section: Resultsmentioning

confidence: 99%

Alleviation of cisplatin-induced neuropathic pain, neuronal apoptosis, and systemic inflammation in mice by rapamycin

Alotaibi

Al-Aqil

Alqahtani

et al. 2022

Front. Aging Neurosci.

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Platinum-based chemotherapeutic treatment of cancer patients is associated with debilitating adverse effects. Several adverse effects have been well investigated, and can be managed satisfactorily, but chemotherapy-induced peripheral neuropathy (CIPN) remains poorly treated. Our primary aim in this study was to investigate the neuroprotective effect of the immunomodulatory drug rapamycin in the mitigation of cisplatin-induced neurotoxicity. Pain assays were performed in vivo to determine whether rapamycin would prevent or significantly decrease cisplatin-induced neurotoxicity in adult male Balb/c mice. Neuropathic pain induced by both chronic and acute exposure to cisplatin was measured by hot plate assay, cold plate assay, tail-flick test, and plantar test. Rapamycin co-treatment resulted in significant reduction in cisplatin-induced nociceptive-like symptoms. To understand the underlying mechanisms behind rapamycin-mediated neuroprotection, we investigated its effect on certain inflammatory mediators implicated in the propagation of chemotherapy-induced neurotoxicity. Interestingly, cisplatin was found to significantly increase peripheral IL-17A expression and CD8- T cells, which were remarkably reversed by the pre-treatment of mice with rapamycin. In addition, rapamycin reduced the cisplatin-induced neuronal apoptosis marked by decreased neuronal caspase-3 activity. The rapamycin neuroprotective effect was also associated with reversal of the changes in protein expression of p21Cip1, p53, and PUMA. Collectively, rapamycin alleviated some features of cisplatin-induced neurotoxicity in mice and can be further investigated for the treatment of cisplatin-induced peripheral neuropathy.

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Section: Resultsmentioning

confidence: 99%

Alleviation of cisplatin-induced neuropathic pain, neuronal apoptosis, and systemic inflammation in mice by rapamycin

Alotaibi

Al-Aqil

Alqahtani

et al. 2022

Front. Aging Neurosci.

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“…The fact that DNA damage is observed in pre-manifest individuals [15], and precedes mitochondrial dysfunction in patient cells [14] and aggregate formation in a mouse model [17], suggests that DNA damage is not a downstream consequence, but may contribute to pathogenesis. It is therefore unclear if the DNA repair pathways implicated in HD cause generalized damage before or after increased somatic expansion, or to what extent each damaging effect contributes to disease progression [8,9,18]. If reducing somatic expansion ameliorates disease, this would suggest that somatic expansion has a key role in disease pathology.…”

Section: Hd Gwas Brings Unbiased Hypotheses Back To Huntington's Diseasementioning

confidence: 99%

DNA Repair in Huntington’s Disease and Spinocerebellar Ataxias: Somatic Instability and Alternative Hypotheses

Maiuri

Hung

Suart

et al. 2021

JHD

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The use of genome wide association studies (GWAS) in Huntington’s disease (HD) research, driven by unbiased human data analysis, has transformed the focus of new targets that could affect age at onset. While there is a significant depth of information on DNA damage repair, with many drugs and drug targets, most of this development has taken place in the context of cancer therapy. DNA damage repair in neurons does not rely on DNA replication correction mechanisms. However, there is a strong connection between DNA repair and neuronal metabolism, mediated by nucleotide salvaging and the poly ADP-ribose (PAR) response, and this connection has been implicated in other age-onset neurodegenerative diseases. Validation of leads including the mismatch repair protein MSH3, and interstrand cross-link repair protein FAN1, suggest the mechanism is driven by somatic CAG instability, which is supported by the protective effect of CAA substitutions in the CAG tract. We currently do not understand: how somatic instability is triggered; the state of DNA damage within expanding alleles in the brain; whether this damage induces mismatch repair and interstrand cross-link pathways; whether instability mediates toxicity, and how this relates to human ageing. We discuss DNA damage pathways uncovered by HD GWAS, known roles of other polyglutamine disease proteins in DNA damage repair, and a panel of hypotheses for pathogenic mechanisms.

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“…At follow-up (T1), approximately 1 year after the clinical onset of HD, LTL values were further reduced by 14% from the baseline and 34% from the control LTL values. LTL in HD mutation carriers was examined in several studies [ 26 , 29 , 30 , 31 ], all showing significantly lower LTL in manifest HD subjects than observed in the controls. Our previous study [ 26 ] reported the first indication of reduced LTL in pre-HD patients.…”

Section: Discussionmentioning

confidence: 99%

“…LTL in HD has been investigated in several studies and found to be shorter in HD patients than in controls [ 26 , 29 , 30 , 31 ]. In a previous study [ 26 ], we observed shorter leukocyte telomeres even in the pre-manifest HD (pre-HD) subjects compared to the controls.…”

Section: Introductionmentioning

confidence: 99%

Leukocyte Telomere Length as Potential Biomarker of HD Progression: A Follow-Up Study

Scarabino

Veneziano

Mantuano

et al. 2022

IJMS

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The identification of biomarkers for neurodegenerative disorders such as Huntington’s disease (HD) is crucial for monitoring disease progression and therapeutic trial outcomes, especially in the pre-manifest disease stage (pre-HD). In a previous study, we observed that leukocyte telomere length (LTL) was strongly correlated with the estimated time to clinical onset in pre-HD subjects. To validate this hypothesis, we designed a follow-up study in which we analyzed LTL in 45 pre-HD stage subjects at baseline (T0) and then again after clinical onset at follow-up (T1); the follow-up interval was about 3 years, and the CAG range was 39–51 repeats; 90 peripheral blood mononuclear cell samples (PBMCs) were obtained from the Enroll-HD biorepository. In pre-HD subjects at T0, LTL was significantly reduced by 22% compared to the controls and by 14% from T0 at T1. No relationship was observed between the LTL and CAG numbers in subjects carrying different CAG repeats at T0 and at T1, suggesting that LTL reduction occurs independently of CAG number in pre-HD subjects. ROC curve analysis was used to test the validity of LTL as a potential biomarker of HD progression and showed that LTL measurement is extremely accurate in discriminating pre-HD subjects from the controls and even pre-HD from manifest HD, thus yielding a robust prognostic value in pre-HD subjects.

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Telomere length analysis on leukocytes derived from patients with Huntington Disease

Cited by 13 publications

References 36 publications

Alleviation of cisplatin-induced neuropathic pain, neuronal apoptosis, and systemic inflammation in mice by rapamycin

Alleviation of cisplatin-induced neuropathic pain, neuronal apoptosis, and systemic inflammation in mice by rapamycin

DNA Repair in Huntington’s Disease and Spinocerebellar Ataxias: Somatic Instability and Alternative Hypotheses

Leukocyte Telomere Length as Potential Biomarker of HD Progression: A Follow-Up Study

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