A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor neurons, leading to paralysis and eventually death. Symptomatic treatments such as inhibition of salivation, alleviation of muscle cramps, and relief of spasticity and pain still play an important role in enhancing the quality of life. To date, riluzole and edaravone are the only two drugs approved by the Food and Drug Administration for the treatment of ALS in a few countries. While there is adequate consensus on the modest efficacy of riluzole, there are still open questions concerning the efficacy of edaravone in slowing the disease progression. Therefore, identification of novel therapeutic strategies is urgently needed. Impaired autophagic process plays a critical role in ALS pathogenesis. In this review, we focus on therapies modulating autophagy in the context of ALS. Furthermore, stem cell therapies, gene therapies, and newly-developed biomaterials have great potentials in alleviating neurodegeneration, which might halt the disease progression. In this review, we will summarize the current and prospective therapies for ALS.

Keywords: Amyotrophic lateral sclerosis; Autophagy; Gene editing; Motor neurons; Stem cells.

Fig. 1

General autophagy process and targets for potential drugs inducing autophagy. Autophagy can be induced by stress, energy deficiency, increased intracellular Ca²⁺, etc., through inhibition of the mTOR complex and subsequent activation of the ULK complex. The class III PI3K complex can be phosphorylated by ULK, subsequently catalyzing PI into PI3P and initiating autophagy. Atg9 vesicles are released from the Golgi complex and recruit the PI3K complex to downstream autophagy-related proteins. The Atg12-Atg5-Atg16L complex and LC3 are ubiquitin ligases that are indispensable for membrane elongation and closure. LC3 can be cleaved by Atg4, and the generated LC3-I binds with PE, which is mediated by the Atg12-Atg5-Atg16L complex, localized on the membranes of autophagosomes. The dynein-dynactin complex mediates the transportation of organelles along the microtubule. Mature vesicles labeled by LC3 are distributed along microtubules and LC3 colocalizes with dynein-dynactin complex. mSOD1 alters the cellular localization of dynein and inhibits the dynein-dynactin complex, impeding the transportation of autophagosomes. TFEB is regulated by mTORC1 to mediate the expression of autophagy and lysosome-related protein (atg9B and LAMP1), which in turn affects the formation of autolysosome. mSOD1 also interferes with the expression of TFEB. Rab7 regulates the formation and maturation of autolysosome, and interacts with C9ORF72. Lithium and n-butylidenephthalide enhance autophagy by inhibiting PI3K and GSK-3β, Rapamycin and Torkinib induce autophagy by inhibiting mTORC1, while carbamazepine, verapamil and trehalose initiate autophagy by activating AMPK. Also, trehalose regulates the phosphorylation and translocation of TFEB. It has been reported that ropinirole induces autophagy through a Beclin-1-dependent pathway. HDAC6 can control the fusion of autophagosomes and lysosomes. mTORC1: mechanistic target of rapamycin complex 1, ULK1: unc-51-like kinase 1, AMPK: AMP-activated protein kinase, PI3K: phosphoinositide 3-kinase, GSK-3β: glycogen synthase kinase-3β, PI: phosphatidylinositol, PI3P: phosphatidylinositol-3-phosphate, Atg: autophagy-related protein, LC3: microtubule-associated protein 1A/1B-light chain 3, PE: phosphatidyl ethanolamine, mSOD1: mutant SOD1, TFEB: transcription factor EB, LAMP1: lysosomal-associated membrane protein 1, Rab7: Ras-related protein 7