Secondary Metabolites of Lichens as Both Anti-aggregative and Antioxidant Agents in Tauopathies

Abstract

This commentary described our findings of parietin, an anthraquinone, isolated from Ramalina terebrata as inhibitor of tau protein. Moreover, we considered important to link tauopathies with reactive oxygen species since oligomers and fibril-forming elements are responsible for activating reactive oxygen species, which cause inflammatory response and neurodegeneration. Together, we considered important to find naturally occurring compounds that might be able to stop aggregation and reduce ROS cells damage.Keywords: Tauopathies; Secondary metabolites; Lichens; Reactive oxygen species; Inflammatory response; Neurodegeneration Tauopathies and NeurotoxicityTaoupathies are neurodegenerative disorders involving tau protein, such as progressive nuclear palsy (PSP), corticobasal degeneration (CBD), Pick´s disease among others. Tau is an unfolded protein which is found mainly in axons of mature and physiologically is involved in microtubule stability and axonal transport [1]. However, once tau becomes hyperphosphorylated it detaches from microtubule starting the aggregation process [2,3]. Pathological tau aggregates are able to activate glia cells that release cytotoxic factors, which cause pro inflammatory cytokines such as TNF-α, IL-1 and IL-6 and chemokines [4]. Tau phosphorylation is increased in both physiologically and pathological state [5], however phosphorylation is increased during development, suggesting that process is needed for neuronal plasticity [6]. Tau phosphorylation is an event highly regulated by kinases and phosphatases. Its balance is deregulated due to several stimuli such as oxidative stress [7]. Tau is able to form paired helical filaments closely related to neurofibrillary tangles [8,9]. Hyperphosphorylated tau protein is found in patients suffering with tauopathies in cerebrospinal fluid (CNS), which correlates well with hypocampal atrophy [10]. In addition, tauopathies have tau hyperphosphorylated as a hallmark; however, the degree of phosphorylation differs among them. In addition, it is important to notice that there is no single phosphorylation site associated to a particular tauopathy [5]. Moreover, tau has the propensity to form aggregates, since inside the full length protein (441 aminoacids) resides a region known as 4R (four microtubule binding domain) containing two hexapeptides 275 VQIINK 280 and 306 VQIVYK 311 both associated to β sheet formation [11]. Increased tau phosphorylation decreased its binding for microtubules. These species prone to form aggregates which are toxic in both cell and transgenic mouse model [12,13]. Despite that fact, there are evidences showing that soluble species and pre fibrils which are more related to toxicity [14]. An interesting UV raman spectroscopy study showed that at early stages, within the first hour, fibrillar aggregates possess a mixture of β-sheet and disordered content. Afterward, the UVRR spectra shows a consolidation in fibril structure, augmenting the content of β sheet [15], interesting is to remark that toxicity apparently reli...

Stereocalpin B, a New Cyclic Depsipeptide from the Antarctic Lichen Ramalina terebrata

“…Metabolites 2022, 12, 141 2 of 11 usimines A-C were reported to have antibacterial activity against B. subtilis [11], ramalin to have anti-inflammatory, anticancer, and antioxidant activity [9,12], and parietin was shown to serve as both anti-aggregative and antioxidant agents in tauopathies [10,13].…”

“…Lichens are well known for their composition of depsides and dibenzofurans as major secondary metabolites, where depsides are reported to have antioxidant and antifungal activities [2,4], and dibenzofurans are known to exhibit anticancer, antifungal, and antineoplastic properties [5][6][7]. The Antarctic lichen, Ramalina terebrata, is also known to possess various secondary metabolites such as usnic acid derivatives, ramalin, and anthraquinones [1,[8][9][10]. Derived from R. terebrata, usnic acid, and usimines A-C were reported to have antibacterial activity against B. subtilis [11], ramalin to have anti-inflammatory, anticancer, and antioxidant activity [9,12], and parietin was shown to serve as both anti-aggregative and antioxidant agents in tauopathies [10,13].…”

“…The Antarctic lichen, Ramalina terebrata, is also known to possess various secondary metabolites such as usnic acid derivatives, ramalin, and anthraquinones [1,[8][9][10]. Derived from R. terebrata, usnic acid, and usimines A-C were reported to have antibacterial activity against B. subtilis [11], ramalin to have anti-inflammatory, anticancer, and antioxidant activity [9,12], and parietin was shown to serve as both anti-aggregative and antioxidant agents in tauopathies [10,13].…”