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Amyotrophic Lateral Sclerosis and Autophagy: Dysfunction and Therapeutic Targeting

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Amyotrophic Lateral Sclerosis and Autophagy: Dysfunction and Therapeutic Targeting cells Review Amyotrophic Lateral Sclerosis and Autophagy: Dysfunction and Therapeutic Targeting Azin Amin, Nirma D. Perera, Philip M. Beart, Bradley J. Turner and Fazel Shabanpoor * Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3052, Australia; [email protected] (A.A.); nirma.perera@florey.edu.au (N.D.P.); phil.beart@florey.edu.au (P.M.B.); bradley.turner@florey.edu.au (B.J.T.) * Correspondence: [email protected] Received: 5 October 2020; Accepted: 1 November 2020; Published: 4 November 2020 Abstract: Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more than 40 different ALS-causing mutations, the accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is the main pathological hallmark in all cases of ALS. These protein aggregates are proposed to disrupt cellular processes and ultimately result in neurodegeneration. One of the main reasons implicated in the accumulation of protein aggregates may be defective autophagy, a highly conserved intracellular “clearance” system delivering misfolded proteins, aggregates, and damaged organelles to lysosomes for degradation. Autophagy is one of the primary stress response mechanisms activated in highly sensitive and specialised neurons following insult to ensure their survival. The upregulation of autophagy through pharmacological autophagy-inducing agents has largely been shown to reduce intracellular protein aggregate levels and disease phenotypes in different in vitro and in vivo models of neurodegenerative diseases. In this review, we explore the intriguing interface between ALS and autophagy, provide a most comprehensive summary of autophagy-targeted drugs that have been examined or are being developed as potential treatments for ALS to date, and discuss potential therapeutic strategies for targeting autophagy in ALS. Keywords: motor neuron disease; amyotrophic lateral sclerosis; autophagy; therapeutics 1. Introduction 1.1. Amyotrophic Lateral Sclerosis Motor neuron (MN) diseases are a group of neurodegenerative diseases where MNs selectively degenerate. Amyotrophic Lateral Sclerosis (ALS, known as motor neuron disease in United Kingdom and Australia, and Lou Gehrig’s disease in the USA) is the most common form [1,2], with approximately 1–2 newly diagnosed cases in every 100,000 people internationally every year [3]. In ALS, both the upper MNs in the motor cortex and the associated corticospinal tract, and the lower MNs in the brainstem and spinal cord selectively degenerate. As a result, neuromuscular function deteriorates, evoking weakness, muscle wasting, and paralysis [2,4–6]. In the majority of cases, the disease manifests itself between the ages of 50 and 60 [5]. Typically, 3–4 years after symptom onset, respiratory muscles also atrophy, culminating in death [2,4–6]. However, in approximately one-third of patients where symptoms begin at the bulbar level with dysarthria and dysphagia, survival is shortened to an average of 2 years [7–9]. ALS is a complex and heterogeneous disorder with likely multiple causes. More than 90% of cases are sporadic (SALS) with no obvious family history of disease, and 10% of cases are familial (FALS) with one or more identifiable genetic mutations (Figure1). The first discovered ALS-associated gene Cells 2020, 9, 2413; doi:10.3390/cells9112413 www.mdpi.com/journal/cells Cells 2020, 9, 2413x FOR PEER REVIEW 2 of 32 30 (FALS) with one or more identifiable genetic mutations (Figure 1). The first discovered ALS- wasassociatedsuperoxide gene dismutase was superoxide 1 (SOD1) [dismutase10]. However, 1 (SOD1) more recently, [10]. However, an intronic more hexanucleotide recently, an (GGGGCC) intronic hexanucleotiderepeat expansion (GGGGCC) in the non-coding repeat expansio segmentn of in the thechromosome non-coding 9 opening segment reading of the frame chromosome 72 (C9orf72) 9 openinggene wasreading identified frame 72 as (C9orf72) the most gene prevalent was identified cause of FALS as the [11 most,12]. prevalent After C9orf72 causeand of SOD1FALS, the[11,12]. two After most C9orf72common and mutations SOD1, the implicated two most in common FALS are mutations in the genes impTARlicated DNA in FALS binding are partner in the 43 genes (TARDBP) TAR DNA[13] bindingand fused partner in sarcoma 43 (TARDBP) (FUS) [14 [13],15]. and fused in sarcoma (FUS) [14,15]. Figure 1. TheThe prevalence prevalence of of the the most commonly know knownn genetic causes of Amyotrophic Lateral Sclerosis (ALS). Other genes that ar aree more rarely associated with AL ALSS are not included in the diagram above are: sequestosome 1 1 (SQSTM1), (SQSTM1), dynactin dynactin su subunitbunit 1 1 (DCTN1), (DCTN1), VAMP VAMP as associatedsociated protein B and C (VAPB), D-amino acid oxidase (DAO), TATA-box TATA-box binding protein associated factor 15 15 (TAF15), (TAF15), ubiquilin 22 (UBQLN2), (UBQLN2), heterogenous heterogenous nuclear nuclear ribonucleoprotein ribonucleoprotein A1 (hnRNPA1), A1 (hnRNPA1), heterogenous heterogenous nuclear nuclearribonucleoproteins ribonucleoproteins A2/B1 (hnRNPA2B1), A2/B1 (hnRNPA2B1), matrin 3 (MATR3),matrin 3 (MATR3), tubulin alpha tubulin 4a (TUBA4A), alpha 4a (TUBA4A), sec1 family sec1domain family containing domain 1 containing (SCFD1), myelin 1 (SCFD1), associated myelin oligodendrocyte associated oligodendrocyte basic protein (MOBP), basic protein chromosome (MOBP), 21 chromosomeopen reading frame21 open 2 (C21orf2),reading frame cyclin 2 F (C21orf2), (CCNF), NIMA cyclin related F (CCNF), kinase NIMA 1 (NEK1), related neurofilament kinase 1 (NEK1), heavy (NEFH),neurofilament dnaJ heat heavy shock (NEFH), protein dnaJ family heat (DNAJ), shock EWSprotein RNA family binding (DNAJ), protein EWS 1 (EWSR1), RNA binding senataxin protein (SETX), 1 (EWSR1),calcium- responsivesenataxin (SETX), transactivator calcium- (CREST), responsive elongator transactivator acetyltransferase (CREST), el complexongator subunitacetyltransferase 3 (ELP3), complexcharged multivesicularsubunit 3 (ELP3), body charged protein multivesicular 2B (CHMP2B), body alsin rhoprotein nucleotide 2B (CHMP2B) exchange, alsin factor rho ALS2 nucleotide (ALS2), exchangesigma non-opioid factor ALS2 intracellular (ALS2), receptor sigma 1 (SIGMARI),non-opioid FIG4intracellular phosphoinositide receptor 5-phosphatase1 (SIGMARI),(FIG4), FIG4 phosphoinositidespastic paraplegia 115-phosphatase (SPG11), peripherin (FIG4), (PRPH), spasti neuropathyc paraplegia target 11 esterase (SPG11), (NTE), peripherin serum paraoxonase (PRPH), neuropathyand arylesterase target 1-3 esterase (PON1-3), (NTE), cholinergic serum receptorparaoxonase nicotinic and alphaarylesterase 3 (CHRNA3), 1-3 (PON1-3), cholinergic cholinergic receptor receptornicotinic nicotinic alpha 4 (CHRNA4), alpha 3 (CHRNA3), cholinergic cholinergic receptor nicotinic receptor beta nicotinic 4 (CHRNB4), alpha 4 (CHRNA4), erb-b2 receptor cholinergic tyrosine receptorkinase 4 (ERBB4),nicotinic coiled-coil-helix-coiled-coil-helixbeta 4 (CHRNB4), erb-b2 receptor domain tyrosine containing kinase 104 (ERBB4), (CHCHD10), coiled-coil-helix- amyotrophic coiled-coil-helixlateral sclerosis 3domain (ALS3), amyotrophiccontaining 10 lateral (CHCHD sclerosis10), 7amyotrophic (ALS7), amyotrophic lateral sclerosis lateral sclerosis 3 (ALS3), 6-21 (ALS6-21),amyotrophic amyotrophic lateral sclerosis lateral 7 sclerosis-frontotemporal(ALS7), amyotrophic lateral dementia sclerosis (ALS-FTD) 6-21 (ALS6-21), [16]. amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) [16]. SALS and FALS are clinically indistinguishable, and the predominant cytoplasmic accumulation of ubiquitinated,SALS and FALS hyaline, are clinically and skein-like indistinguishable, aggregates and within the predominant degenerating cytoplasmic MNs and glialaccumulation cells is a ofhallmark ubiquitinated, of both formshyaline, of ALSand [skein-like17–20]. With aggreg the exceptionates within of degenerating SOD1- and FUS-linked MNs and ALS,glial thecells major is a pathologicalhallmark of both protein forms in of all ALS cases [17–20]. of ALS With is TDP-43 the exception and analysis of SOD1- of post-mortemand FUS-linked tissues ALS, fromthe major ALS patientspathological and protein mouse modelsin all cases has establishedof ALS is TDP-43 that there and is analysis a direct of correlation post-mortem between tissues MN from loss ALS and TDP-43patients pathologyand mouse [21 models,22]. has established that there is a direct correlation between MN loss and TDP-43Intracellular pathology protein[21,22]. aggregates form when the level of misfolded proteins reaches a critical concentration,Intracellular subsequently protein aggregates assembling form into when small the soluble level of oligomers. misfolded Eventually,proteins reaches with timea critical and concentration,increasing concentration subsequently of proteins, assembling oligomers into small convert soluble into theoligom moreers. metabolically Eventually, stablewith time insoluble and increasingaggregates concentration [23–25]. According of proteins, to the“seeding-nucleation” oligomers convert into model, the more oligomerisation metabolically is a stable slow processinsoluble as aggregatesit is thermodynamically [23–25]. According unfavourable. to the “seeding-nucleation” However, once an oligomeric model, oligomerisation seed is formed, is it a grows slow process rapidly as it is thermodynamically
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