Leukocyte telomere shortening in Huntington's disease

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat. Though symptom onset commonly occurs at midlife and inversely correlates with the CAG repeat expansion, age at clinical onset and progression rate are variable. In the present study we investigated the relationship between leukocyte telomere length (LTL) and HD development. LTL was measured by real-time PCR in manifest HD patients (HD, n=62), pre-manifest HD patients (pre-HD, n=38), and age-matched controls (n= 76). Significant LTL differences were observed between the three groups (p< 0.0001), with LTL values in the order: HD <pre-HD <controls. The relationship between LTL and age was different in the three groups. An inverse relationship between mean LTL and CAG repeat number was found in the pre-HD (p=0.03). The overall data seem to indicate that after age 30 years, LT begins to shorten markedly in pre-HD patients according to CAG number and increasing age, up to the values observed in HD. This very suggestive picture allowed us to hypothesize that in pre-manifest HD, LTL could be a measure of time to clinical HD onset. The possible use of LTL as a reliable biomarker to track HD development and progression was evaluated and discussed.

Circulating U13 small nucleolar RNA as a candidate biomarker for Huntington’s disease

“…Indeed, beyond ribosomal biogenesis and RNA metabolism, SNORD13 appears to be involved in a wide range of genomic activities associated with HD pathophysiology (Figure 4, Supplementary Table 1): chromatin remodeling via histone acetylation and methylation ( SIRT6, EP300, TAF1, CHD1, KDM5A-B etc . ) ; telomere length maintenance ( DKC1,HRNPU, VPRBP) 5 ; DNA repair and damage response ( ERCC6, BAZ1B, FANCD2, TOPBP1) 6,24 ; direct modulation of Homeobox ( HOXA1-7, DLX1-2, OTX2 and others) and Zinc-finger proteins ( SNAI2, SP1-2, ZMIZ2 and others) 31 . We also identified three miRNAs (hsa-miR-455-5p, hsa-miR-342-3p, hsa-miR-377-3p) that may cooperate with U13 snoRNA in regulating gene expression, as being possibly affected in HD; stochastic computational analyses might help further explain these relationships, as piloted in Multiple Sclerosis pathogenesis modeling 32 , in COVID epidemic waves stability evaluation 33 , and in many other complex problems.…”

“…A more recent focus was given to more easily measurable biomarkers, coming from peripheral leucocytes and plasma, that are cheaper, less invasive and potentially more adept to obtain 3 longitudinal profiles. Among these, the leukocyte telomere length (LTL) shorten remarkably in pre-HD, being a possible measure of time to clinical onset 5 . Changes in histone variant pγ-H2AX, as a component of the DNA damage responses, in peripheral blood mononuclear cells (PBMCs), proved to be an informative, potentially reversible biomarker in pre-HD 6 .…”

Circulating Exosomal miRNA as Diagnostic Biomarkers of Neurodegenerative Diseases

“…Progress has been made in circulating biomarkers of diagnosis of HD, with plasma NfL reported to be significantly increased in HD patients (Tabrizi et al, 2013). Leukocyte telomere length values were significantly decreased in HD and might be a reliable biomarker to track HD progression (Scarabino et al, 2019). In the PREDICT-HD study, the researchers suggested that six miRNAs-miR-135b-3p, miR-140-5p, miR-520f-3p, miR-3928-5p, miR-4317, and miR-8082were significantly increased in presymptomatic HD patients and could be potential biomarkers for the early diagnosis of HD (Reed et al, 2018).…”

MicroRNAs in Huntington’s Disease: Diagnostic Biomarkers or Therapeutic Agents?

“…Thus, LTL might be a reliable biomarker to track HD progression. However, a well-designed follow-up study would be useful to verify the actual relationship between LTL and HD onset (Scarabino et al, 2019). Levels of the proinflammatory cytokine IL-6 have also been reported as a biomarker to diagnose HD (Chang et al, 2015); however, the sensitivity and specificity of the diagnosis remain to be confirmed.…”