Alpha-synuclein in cutaneous small nerve fibers

Abstract

Despite progression in the development of pharmacological therapy, treatment of alpha synucleinopathies, such as Parkinson’s disease (PD) and some atypical parkinsonism syndromes, is still challenging. To date, our knowledge of the mechanisms whereby the pathological form of alpha-synuclein causes structural and functional damage to the nervous system is limited and, consequently, there is a lack of specific diagnostic tools to evaluate pathology in these patients and differentiate PD from other neurodegenerative proteinopathies. Recent studies indicated that alpha-synuclein deposition in cutaneous small nerve fibers assessed by skin biopsies might be a valid disease marker of PD and facilitate early differentiation of PD from atypical parkinsonism syndromes. This observation is relevant since early diagnosis may enable timely treatment and improve quality of life. However, challenges include the necessity of standardizing immunohistochemical analysis techniques and the identification of potential distinct patterns of intraneural alpha-synuclein deposition among synucleinopathies. In this perspective, we explore the scientific and clinical opportunities arising from alpha-synuclein assessment using skin biopsies. These include elucidation of the peripheral nervous system pathology of PD and other synucleinopathies, identification of novel targets to study response to neuroprotective treatment, and improvement of clinical management. Furthermore, we discuss future challenges in exploring the diagnostic value of skin biopsy assessment for alpha-synuclein deposition and implementing the technique in clinical practice.

Should Skin Biopsies Be Performed in Patients Suspected of Having Parkinson’s Disease?

“…Clinical manifestations range from bladder dysfunction over orthostatic hypotension to dyshidrosis, erectile dysfunction, and obstipation. Although diabetes is the most prevalent cause of autonomic fiber dysfunction in more developed countries, targeted fiber damage can also occur in various systemic diseases such as amyloidosis, paraneoplastic syndromes, and infectious diseases and has been shown to be targeted by peripheral synucleinopathies such as PD [ 3 , 18 – 20 ].…”

“…In these small lightly myelinated and unmyelinated nerve fibers, α -synuclein deposits are present even in the early stages of PD as demonstrated by an analysis of skin biopsies immunohistochemically costained for α -synuclein and nerve fibers [ 2 ]. This technique has enabled, for the first time, assessment of synucleinopathic changes in the peripheral nervous system and has been reproduced or modified in several research studies in patients with PD [ 3 – 5 ]. However, the mechanisms whereby synucleinopathic nerve damage relates to central neurodegeneration in later life and how it might play a causative role in PD remain unknown.…”

Current problems and development trends of specific complex methods for the diagnosis of neurotic disorders

“…Среди неинвазивных инструментальных методов исследования наибольшую популярность получили: электроэцефалография, реоэнцефалография, эхоэнцефалография, краниография, томография, электрокардиография и др. В практике современного врача-психиатра встречаются комбинации этих методов и внедрение новых, основанных на акустическом, звуковом и нейрофизиологическом обследовании [24,31,33].…”

“…Меньше всего исследований имеется в отношении объективного скрининга состояний с целью выявления лиц, имеющих факторы риска развития невротических расстройств (напр., повышенное нервно-психическое напряжение, эмоциональную лабильность, вегетативную неустойчивость). В литературе [10,28,31,32,34,35] широко отмечается актуальность экспресс-диагностики невротических расстройств и неврозоподобных состояний на основе определения значимых медицинских параметров ЭЭС, ЭКС и РС.…”

Editorial: Integrity of the Autonomic Nervous System in Psychiatric and Neurological Disorders

“…Functional integrity of the sudomotor and cardiovascular autonomic nervous system can be tested non-invasively using well-established techniques such as quantitative sudomotor axonreflex test, heart rate variability assessment and tilt table test (5). Structural integrity of the autonomic nervous system can be assessed using imaging of autonomic cerebral control centers such as the insular cortex as well as by immunohistochemical analysis of small nerve fibers in cutaneous punch biopsies (6,7). Designing and further advancing these techniques helped improving our pathophysiological understanding of autonomic nervous system disorders and allowed identification of novel diagnostic and therapeutic targets.…”