Can leukocyte telomere shortening be a possible biomarker to track Huntington’s disease progression?

Huntington’s disease (HD): HD is an autosomal dominant neurodegenerative disease, caused by a CAG trinucleotide repeat expansion in the first exon of the HTT gene encoding the huntingtin protein. The mutant protein contains an expanded polyglutamine sequence that confers a toxic gain-of-function and causes neurodegeneration. Moreover, several studies indicate that loss of the normal protein beneficial functions, contribute to the pathology (Schulte and Littleton 2011). Triplet expansion over 40 repeats are fully penetrant and invariably lead to manifest HD in the fourth or fifth decade of life. Clinically, HD is a debilitating, incurable disorder in which no symptoms reveal genetic status (presymptomatic phase) until signs and symptoms of motor impairment, such as poor coordination or slight involuntary movements and subtle changes in eye movements, begin to appear (prodromal phase). Often the prodromal phase (up to 15 years before the full-blown disorders) includes psychological and psychiatric alterations as irritable mood, depression, difficulty in learning new information or mental planning; nonetheless, affected individuals are usually able to perform their ordinary activities and to continue work. With progression of the disease, however, involuntary jerking or twitching movements (choreic movement) become exacerbated, making walking, speaking, and swallowing increasingly difficult. Also, cognitive and psychiatric symptoms are worsening until dementia (Paulsen, 2010). The clinical diagnosis of HD is based chiefly on the presence of motor signs and symptoms according to the diagnostic confidence level from the Unified Huntington’s Disease rating scale. This standard assessment tool for grading HD symptom severity is based on two relevant subscores: total functional capacity, which tracks the ability to perform daily activities, and the total motor score, which specifically tracks motor abilities (https://www.ncbi.nlm.nih.gov/books/NBK1305/). The diagnostic confidence level ranges from 0 (asymptomatic) to 4 (motor impairments as unambiguous signs of HD). When a clinical diagnosis is established, the disease is manifest and becomes more and more devastating with time. In late stages, motor disability progress from hyperkinesia/chorea to severe hypokinesia/rigidity, rendering the affected individual often totally dependent, mute, and incontinent. Since, right now, there are no disease-modifying treatments, the disease slowly progresses toward death within 15 to 18 years after its onset. Though no treatment can alter its course, the prodromal stage is fundamental for evaluating the wide spectrum of signs and symptoms of disease progression. In addition, earlier stages of dysfunction offer a potential window for intervention or modification of pathogenic mechanisms. The duration of these stages varies among individuals. The length of CAG repeat is negatively correlated with age at disease onset. Models based on biological age and CAG repeat length are available to approximately estimate the years until onset in mutation carriers (Langbehn et al., 2010). Such testing, although useful, is not accurate in predicting age at clinical onset because CAG length accounts for only about 50–70% of the variation within a range of 40 to 55 CAG repeats. The residual variance is probably due to genetic, stochastic, and environmental factors. Given this variance, there is growing interest in HD research to search for phenotype modifier genes and biomarkers, identify specific changes or “stages” of disease progression, predict disease onset, and accurately track disease progression in premanifest HD (Gusella et al., 2014). Telomeres as HD biomarkers: The possibility of presymptomatic genetic testing in HD opens the way for evaluating potential disease-modifying treatments in the premanifest phase. Biomarkers that reflect underlying disease processes or progression are needed to monitor changes in clinically asymptomatic individuals. No studies to date have yielded validated biomarkers that can accurately predict either age at HD onset or disease progression, although the neurofilament light protein appears extremely promising (Silajdzic and Bjorkqvist, 2018). At present there are no effective treatments in clinical practice that can prevent the disease, halt its progression or delay its onset. Nonetheless, as the future holds promise for disease-modifying strategies, there is a need for reliably assessable disease progression biomarkers, as well as markers to detect treatment-related changes. Ideally, a biomarker will be closely linked to the pathophysiology of the disease, reliable, accurate, sensitive, specific, reproducible, inexpensive, non-invasive, and acceptable for the patient (Silajdzic and Bjorkqvist, 2018). Easily accessible peripheral biomarkers from peripheral blood mononuclear cells and plasma have gained increasing attention. Our recent work seems to indicate that leukocyte telomere(definition) length (LTL) could possess several of the characteristics required of an ideal biomarker to track HD progression (Scarabino et al., 2019). Telomeres are the terminal ends of the chromosomes and play a role in preserving genome stability. Telomere shortening occurs progressively with repeated cell division because of the inability of DNA polymerase to replicate the 3′ end of the DNA strand. A cellular multiprotein complex, called telomerase, counteracts telomere shortening, but its activity, usually present in the early stages of embryonic development, is silenced in several human somatic tissues immediately after birth. As a consequence, the telomeres shorten progressively with increasing age in the replicating cells of adult tissues (Blackburn et al., 2015). This phenomenon may indicate cellular senescence(definition) and reflect an organism’s biological age. Peripheral blood mononuclear cells provide an easily accessible source of cells in which telomere length can be analyzed. Shortened LTL has been found to be associat