Exploring the Role of ACE2 as a Connecting Link between COVID-19 and Parkinson's Disease

Abstract

Coronavirus disease 2019 (COVID-19) is frequently accompanied by neurological manifestations such as headache, delirium, and epileptic seizures, whereas ageusia and anosmia may appear before respiratory symptoms. Among the various neurological COVID-19-related comorbidities, Parkinson's disease (PD) has gained increasing attention. Some cases of PD disease have been linked to COVID-19, and both motor and non-motor symptoms in Parkinson's disease patients frequently worsen following SARS-CoV-2 infection. Although it is still unclear whether PD increases the susceptibility to SARS-CoV-2 infection or whether COVID-19 increases the risk of or unmasks future cases of PD, emerging evidence sheds more light on the molecular mechanisms underlying the relationship between these two diseases. Among them, angiotensin-converting enzyme 2 (ACE2), a significant component of the renin-angiotensin system (RAS), seems to play a pivotal role. ACE2 is required for the entry of SARS-CoV-2 to the human host cells, and ACE2 dysregulation is implicated in the severity of COVID-19-related acute respiratory distress syndrome (ARDS). ACE2 imbalance is implicated in core shared pathophysiological mechanisms between PD and COVID-19, including aberrant inflammatory responses, oxidative stress, mitochondrial dysfunction, and immune dysregulation. ACE2 may also be implicated in alpha-synuclein-induced dopaminergic degeneration, gut-brain axis dysregulation, blood-brain axis disruption, autonomic dysfunction, depression, anxiety, and hyposmia, which are key features of PD.

Keywords: COVID-19 pandemic; dopaminergic degeneration; neurodegeneration; neuroinflammation.

Figure 1

The relationship between the dysregulation of ACE2 and PD. RAS and ACE2 dysregulation play a critical role in PD pathogenesis by modulating apoptosis, mitochondrial function, oxidative stress, neuroinflammation, and autoimmunity. Since these mechanisms are also involved in COVID-19 pathophysiology, it can be hypothesized that ACE2 represents a key molecule connecting these two conditions. ACE2: angiotensin converting enzyme 2; AT1R: angiotensin II type 1 receptor; Nox4: NADPH oxidase 4; PD: Parkinson’s disease; RAS: renin angiotensin system.

Figure 2

ACE2 as the underlying connecting link between COVID-19 and Parkinson’s disease. Proposed ACE2 mechanisms underlying the relationship between COVID-19 and Parkinson’s disease: SARS-CoV-2 enters the human host cells via its essential cellular receptor, ACE2. ACE2 is located in several tissues, including the lungs, the olfactory epithelium, and the intestinal wall. SARS-CoV-2 can enter the brain through (1) the olfactory and vagus nerve via retrograde axonal transport or (2) the bloodstream via a disrupted blood–brain barrier. ACE2 is also located in the epithelial cells of the blood–brain barrier, where it could facilitate the entry of SARS-CoV-2 into the brain. ACE2 may be implicated in several pathophysiological mechanisms underlying PD pathogenesis, including neuroinflammation, mitochondrial dysfunction, dopaminergic degeneration, oxidative stress, autophagy dysregulation, enhanced apoptosis, alpha-synuclein-induced cell death, and autoimmunity, such as the generation of ACE2 and AT1R autoantibodies. SARS-CoV-2 may create a pro-inflammatory microenvironment in the brain, which may in turn promote neuronal degeneration. Neuroinflammation and degeneration may be initiated in the olfactory bulb and dorsal motor nucleus of the vagus nerve in the brainstem and then reach the dopaminergic neurons in the substania nigra pars compacta. This process follows the Braak stages. Potential ACE2-related links include older age, male sex, gut microbiome dysregulation, diabetes, smoking, depression and anxiety, autonomic dysfunction, and hyposmia [65,80,81,82,83,84,85,86].

Figure 3

Specific pathways involved in ACE2 dysregulation as a connecting link between COVID-19 and PD. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/ (accessed on 28 January 2023)). ACE2: angiotensin converting enzyme 2; AT1R: angiotensin II type 1 receptor; COVID-19: coronavirus disease 019; IL-6: interleukin-6; IL-17: interleukin-17; NLRP3: NLR family pyrin domain containing 3; NF-kB: nuclear factor kappa B; PD: Parkinson’s disease; RAS: renin angiotensin system; TNF-α: tumor necrosis factor-α; TNFSF14: tumor necrosis factor superfamily member 14.