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.
Highlights
PI3KI, 3-kinase; PIP3, phosphatidylinositol-3,4,5-triphosphate; GSK3, glycogen synthase kinase 3; TIP60, tat-interactive protein 60 kDa; TSC1–TSC2, tuberous sclerosis complex; synthase kinase 3; TIP60, tat-interactive protein 60 kDa; TSC1–TSC2, tuberous sclerosis complex; Rheb, Ras homolog enriched in brain; mammalian target of rapamycin complex 1 (mTORC1), mammalian target of rapamycin complex I; ULK1, Unc-51 like autophagy activating kinase 1; PI3KIII, class III phosphoinositol 3-kinase; S6K, ribosomal
The negative impact of rapamycin treatment on mutant SOD1 mice was partly attributed to immunosuppression of neuroprotective regulatory T cells [178], suggesting that global mTOR inhibition may not be useful for ALS
Worth noting that autophagic substrates, critically misfolded proteins and aggregates, are not Beclin 1 in SOD1 and SOD1 mice exacerbates disease [86], whereas it improves the phenotype always measured in tissues of ALS mice treated with autophagy-modulating drugs, which is essential of SOD1G86R mice
Summary
Motor neuron (MN) diseases are a group of neurodegenerative diseases where MNs selectively degenerate. C9orf and SOD1, the two most common mutations implicated in FALS are in the genes TAR DNA and fused in sarcoma (FUS). MNs and glial cells is a SALS and FALS are clinically indistinguishable, the predominant accumulation hallmark of both forms of ALS. TDP-43 and analysis of post-mortem tissues from hallmark of both forms of ALS [17,18,19,20]. With the exception of SOD1- and FUS-linked ALS, the major patients and protein mouse models has established that there a direct of correlation between. The exact role of these different aggregates in cells remains unknown They can be initially cytoprotective by sequestering harmful protein species and burying the hydrophobic core of misfolded proteins, as opposed to having them exposed to the hydrophilic environment. Large intracellular aggregates disturb protein homeostasis, trigger cellular stress, and are closely associated with cell degeneration [17,24,25,30,31,32]
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