antioxidants Review Therapeutic Potential of Polyphenols in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Valentina Novak 1, Boris Rogelj 1,2 and Vera Župunski 1,* 1 Chair of Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia; [email protected] (V.N.); [email protected] (B.R.) 2 Department of Biotechnology, Jozef Stefan Institute, SI-1000 Ljubljana, Slovenia * Correspondence: [email protected] Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are severe neu- rodegenerative disorders that belong to a common disease spectrum. The molecular and cellular aetiology of the spectrum is a highly complex encompassing dysfunction in many processes, includ- ing mitochondrial dysfunction and oxidative stress. There is a paucity of treatment options aside from therapies with subtle effects on the post diagnostic lifespan and symptom management. This presents great interest and necessity for the discovery and development of new compounds and therapies with beneficial effects on the disease. Polyphenols are secondary metabolites found in plant-based foods and are well known for their antioxidant activity. Recent research suggests that they also have a diverse array of neuroprotective functions that could lead to better treatments for neurodegenerative diseases. We present an overview of the effects of various polyphenols in cell line and animal models of ALS/FTD. Furthermore, possible mechanisms behind actions of the most researched compounds (resveratrol, curcumin and green tea catechins) are discussed. Citation: Novak, V.; Rogelj, B.; Keywords: ALS; FTD; polyphenols; neurodegeneration; resveratrol; curcumin; catechin; EGCG Župunski, V. Therapeutic Potential of Polyphenols in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Antioxidants 2021, 10, 1328. 1. Introduction https://doi.org/10.3390/antiox With the ageing population, the treatment and management of neurodegenerative 10081328 diseases is a major and increasing challenge for health care systems and societies around the Academic Editor: Stanley Omaye world [1]. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, resulting in deterioration of motor function, and frontotemporal dementia Received: 12 July 2021 (FTD) is a neurodegenerative disorder characterised by changes in personality, behaviour, Accepted: 20 August 2021 and language. The development of both diseases is a progressive and ultimately fatal Published: 23 August 2021 multistep process with a complex genetic and molecular background. Despite extensive research efforts, only two treatment options with limited effects on survival and motor Publisher’s Note: MDPI stays neutral function are currently approved for ALS. The vast majority of compounds researched as with regard to jurisdictional claims in possible ALS therapies until today were found to be ineffective in clinical trials, highlighting published maps and institutional affil- the need for further research [2]. Currently, only symptomatic treatments with limited iations. effects are available for FTD [3]. Polyphenols are natural compounds whose neuroprotective effects have been demon- strated in various models of neurodegenerative diseases such as Alzheimer’s and Parkin- son’s disease. These compounds are being explored for possible dietary intervention and Copyright: © 2021 by the authors. supplementation as preventive measures against neurodegenerative diseases, and also as Licensee MDPI, Basel, Switzerland. possible candidates for therapies to slow disease progression and alleviate symptoms [4]. This article is an open access article Due to the lack of disease-changing treatments for ALS/FTD and the growing interest distributed under the terms and in natural compounds as therapeutic agents, this article reviews an intriguing topic of conditions of the Creative Commons potential use of polyphenols in the development of treatments for ALS/FTD symptoms. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Antioxidants 2021, 10, 1328. https://doi.org/10.3390/antiox10081328 https://www.mdpi.com/journal/antioxidants Antioxidants 2021, 10, 1328 2 of 15 Antioxidants 2021, 10, 1328 2 of 15 1.1.1.1. Amyotrophic Amyotrophic LateralLateral Sclerosis and and Frontotemporal Frontotemporal Dementia Dementia ALSALS isis aa neurodegenerativeneurodegenerative disease disease characte characterisedrised by by progressive progressive loss loss of ofboth both upper upper andand lower lower motormotor neurons.neurons. Initial Initial signs signs of of the the disease disease may may include include weakness weakness of the of the limbs limbs (in(in spinal-onset spinal-onset ALS)ALS) or difficulties difficulties with with speech speech and and swallowing swallowing (in (in bulbar-onset bulbar-onset ALS) ALS) [5]. [5]. DiseaseDisease progressionprogression eventually leads leads to to paralysis paralysis and and death death from from respiratory respiratory failure, failure, on on averageaverage 24 24 to to 5050 monthsmonths afterafter onsetonset [[6–10].6–10]. The worldwide worldwide incidence incidence of of ALS ALS is is 1.75 1.75 with with a reporteda reported mean mean age age at diagnosisat diagnosis between between 51 51 and and 69 69 years years [11 [11,12].,12]. ALS ALS cases cases can can be be divided di- intovided the into familial the familial form of form the diseaseof the disease (fALS, (fAL 5–15%S, 5–15% of patients), of patients), where where there there is a clearis a clear family history,family history, and the and predominant the predominant sporadic sporadic form (sALS) form (sALS) [13]. Frontotemporal [13]. Frontotemporal dementia dementia (FTD) is a(FTD) type ofis dementiaa type of dementia primarily primarily associated associated with alterations with alterations in the frontal in the andfrontal temporal and tem- lobes. Symptomsporal lobes. manifest Symptoms as changes manifest in as behaviour, changes in personality, behaviour, language,personality, and language, motor skills and mo- [14,15]. Thetor incidenceskills [14,15]. ofFTD The isincidence 1.6 and theof FTD mean is age1.6 and of onset the mean is 65 yearsage of [onset16]. FTD is 65 can years be divided[16]. intoFTD one can behavioural be divided into (bvFTD) one behavioural and two language (bvFTD) variants and two (or language primary variants progressive (or primary aphasias (PPA))progressive [14]. Mean aphasias survival (PPA)) time [14]. for Mean most surviv formsal of time FTD for is approximatelymost forms of FTD 8 years is approxi- [17]. Up to mately 8 years [17]. Up to 40% of FTD patients have a family history of the disease [18,19]. 40% of FTD patients have a family history of the disease [18,19]. Clinical, genetic, pathological and biochemical data show that there is an overlap be- Clinical, genetic, pathological and biochemical data show that there is an overlap tween ALS and FTD. First observations that ALS and FTD might be connected were made between ALS and FTD. First observations that ALS and FTD might be connected were in the early 1990s [20,21]. Data show that about half of ALS patients have cognitive im- made in the early 1990s [20,21]. Data show that about half of ALS patients have cognitive pairment and 15% meet the criteria for FTD [22,23]. Similarly, about 30% of patients with impairment and 15% meet the criteria for FTD [22,23]. Similarly, about 30% of patients FTD develop signs of motor dysfunction and 10–15% have ALS [24,25]. The discovery of with FTD develop signs of motor dysfunction and 10–15% have ALS [24,25]. The discovery common genetic causes and biological mechanisms further confirmed that ALS and FTD ofare common closely geneticassociated causes (Figure and 1) biological [5,26]. mechanisms further confirmed that ALS and FTD are closely associated (Figure1)[5,26]. FigureFigure 1.1. Genes involved in in pathologies pathologies along along the the ALS-FTD ALS-FTD spectrum. spectrum. The The most most common common ge- genetic causesnetic causes of the of disease the disease are highlighted are highlighted in bold. in bold. ALSALS andand FTDFTD pathologies are are multistep multistep processe processess that that affect affect many many aspects aspects of cellular of cellular activity.activity. TheThe most prominent prominent pathological pathological hallmark hallmark of both of both ALS ALS and andFTD FTDare changes are changes in inprotein protein homeostasis, homeostasis, including including protein protein misfolding misfolding and aggreg and aggregation,ation, altered altered localisation, localisa- tion,and anddefects defects in autophagic in autophagic and proteasomal and proteasomal degradation. degradation. The combination The combination of these mech- of these mechanismsanisms leads leads to the to formation the formation of toxic of cyto toxicplasmic cytoplasmic inclusions inclusions in motor in neurons motor neurons and sur- and surroundingrounding cells. cells. Proteins Proteins that that predominantly predominantly form form these these structures structures are aretwo two RNA-binding RNA-binding proteins,proteins, TARTAR DNADNA bindingbinding protein (TDP-43, (TDP-43, protein protein product product of ofTARDBPTARDBP), and), and fused fused in in sarcomasarcoma (FUS),(FUS), microtubule-associatedmicrotubule-associated protein tau (gene(gene MAPTMAPT), andand superoxidesuperoxide dismu-dis- tasemutase 1 (SOD1) 1 (SOD1) [27, 28[27,28].]. The The correlation correlation