Hereditary Spastic Paraplegia and Future Therapeutic Directions: Beneficial Effects of Small Compounds Acting on Cellular Stress

Abstract

Hereditary spastic paraplegia (HSP) is a group of inherited neurodegenerative conditions that share a characteristic feature of degeneration of the longest axons within the corticospinal tract, which leads to progressive spasticity and weakness of the lower limbs. Mutations of over 70 genes produce defects in various biological pathways: axonal transport, lipid metabolism, endoplasmic reticulum (ER) shaping, mitochondrial function, and endosomal trafficking. HSPs suffer from an adequate therapeutic plan. Currently the treatments foreseen for patients affected by this pathology are physiotherapy, to maintain the outgoing tone, and muscle relaxant therapies for spasticity. Very few clinical studies have been conducted, and it's urgent to implement preclinical animal studies devoted to pharmacological test and screening, to expand the rose of compounds potentially attractive for clinical trials. Small animal models, such as Drosophila melanogaster and zebrafish, have been generated, analyzed, and used as preclinical model for screening of compounds and their effects. In this work, we briefly described the role of HSP-linked proteins in the organization of ER endomembrane system and in the regulation of ER homeostasis and stress as a common pathological mechanism for these HSP forms. We then focused our attention on the pharmacodynamic and pharmacokinetic features of some recently identified molecules with antioxidant property, such as salubrinal, guanabenz, N-acetyl cysteine, methylene blue, rapamycin, and naringenin, and on their potential use in future clinical studies. Expanding the models and the pharmacological screening for HSP disease is necessary to give an opportunity to patients and clinicians to test new molecules.

Keywords: N-acetyl cysteine; cell stress; guanabenz; hereditary spastic paraplegia; methylene blue; naringenin; rapamycin; salubrinal.

FIGURE 1

Summarized molecular targets of the small molecules as hereditary spastic paraplegia (HSP) therapeutics. (A) Schematic view of the ER-linked HSP proteins and their localization. (B) Guanabenz, salubrinal, and narigenin are involved in the reduction of ER stress, acting on UPR components or Nrf2, the master regulator of antioxidant responses. (C) Rapamycin specifically binds to mTOR and activates autophagy, whereas NAR inhibits TPC channels on lysosomes. (D) NAC is an aminothiol and synthetic precursor of intracellular cysteine and glutathione (GSH), acting as an antioxidant or free radical scavenger. Abbreviations: ER, endoplasmic reticulum; UPR, unfolded protein response; Nrf2, nuclear factor erythroid 2-related factor 2; PERK, protein kinase R-like ER kinase; ATF6, activating transcription factor 6; IRE1, inositol-requiring enzyme 1; eIF2α, eukaryotic initiation factor 2α; eIF2αP, phosphorylated eukaryotic initiation factor 2α; GADD34, growth arrest and DNA damage-inducible protein; mTOR, mammalian target of rapamycin complex 1; ROOH, organic hydroperoxide; cys, cysteine; Cys-Cys, cysteine; cyt, cytochrome c; ROS, reactive oxygen species; TPC, two-pore channel. Created with BioRender.com.

FIGURE 2

Chemical structure of the molecules that could be considered for the treatment of HSP disease.