What, When and How to Measure—Peripheral Biomarkers in Therapy of Huntington’s Disease

Abstract

Among the main challenges in further advancing therapeutic strategies for Huntington’s disease (HD) is the development of biomarkers which must be applied to assess the efficiency of the treatment. HD is a dreadful neurodegenerative disorder which has its source of pathogenesis in the central nervous system (CNS) but is reflected by symptoms in the periphery. Visible symptoms include motor deficits and slight changes in peripheral tissues, which can be used as hallmarks for prognosis of the course of HD, e.g., the onset of the disease symptoms. Knowing how the pathology develops in the context of whole organisms is crucial for the development of therapy which would be the most beneficial for patients, as well as for proposing appropriate biomarkers to monitor disease progression and/or efficiency of treatment. We focus here on molecular peripheral biomarkers which could be used as a measurable outcome of potential therapy. We present and discuss a list of wet biomarkers which have been proposed in recent years to measure pre- and postsymptomatic HD. Interestingly, investigation of peripheral biomarkers in HD can unravel new aspects of the disease pathogenesis. This especially refers to inflammatory proteins or specific immune cells which attract scientific attention in neurodegenerative disorders.

Emerging Roles of Exosomes in Huntington’s Disease

“…Over the past decades, clinical trials targeting the disease modification and symptomatic treatments in HD have begun, a number of these trials have failed and vast number are currently ongoing [46]. Availability of biomarkers, particularly accessible with minimal invasivity, is essential to estimate the treatment efficiency [47].…”

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

“…Our study highlights the unprecedented finding of a potential role of small nucleolar RNAs in HD. The main points related to this result are the following: (i) a circulating SNORD13 is significantly increased in the overt disease compared to the prodromal phase of HD; (ii) the levels of this snoRNA are comparable between healthy individuals and pre-HD status; (iii) this finding seems specific for HD, since three groups of control (healthy people, PP sharing drugs with HD patients, and AD patients) showed normal, comparable values; (iv) the plasma levels of SNORD13 seems to efficiently mark the natural history of HD, correlating with the status of mHTT carrier and the disease duration; (v) the above points (iii) and (iv) suggest that increased levels of SNORD13 in blood mirror pathogenic events in the CNS (though this fact awaits formal demonstration), possibly paving the way for new therapeutic targets; (vi) SNORD13 may become a good peripheral biomarker for clinical purposes in HD; it is indeed easily measurable, inexpensive to test, possibly linked to the pathophysiology of the disease, and reliably quantifiable (being consistent, accurate, sensitive, specific and reproducible) 9 . A possible hypothesis to explain our data is that the elevated plasma level of SNORD13 in HD patients may be due to the nucleolar stress caused by the presence of mutant RNAs that carry an expanded CAG repeat (expanded CAG RNAs).…”

“…Plasma NfL resulted reliable in monitoring disease progression, though less sensitive than CSF NfL 4 . Other studies reported informative results on plasma levels of oxidative stress markers, metabolic markers and immune system products 9 . Recent studies on small non-coding RNAs in plasma from HD patients led to several investigations on circulating micro-RNAs (miRNA) 10–12 .…”

Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease

“…posttranslational modifications [258], proteostasis [259], autophagy [260,261], redox homeostasis [262], metabolism [263,264], HTT mRNA [265,266], Ca 2+ and dopamine signaling [61], inflammation [267], in vitro modelling of HD [268,269], striatal neurogenesis [270], stem cell treatment [271][272][273][274][275][276][277][278][279], electric stimulation therapy [280], network connectivity in presymptomatic HD brain [281], non-motor symptoms [282], gut microbiome [283], human immunodeficiency virus [284], diagnosis [285,286], clinical progression [287], treatment for the symptoms [288], physical therapy [289], psychological interventions [290,291], and management of agitation [292]. Collectively, the previous studies have potential to reveal spatiotemporal and cell-type specific mechanism of HD pathology.…”