In vivo and in silico investigations of the pegylated gold nanoparticle treatment of amyotrophic lateral sclerosis in mice

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal disease that involves the progressive annihilation of motor neurons. In a preclinical setting, sensitive functional testing is required to detect malfunctioning motor behavior in the SOD1^G93A transgenic mouse model of ALS. Earlier, we reported the restoration of motor processivity upon gold nano-chaperon treatment in vitro that was dampened upon the exogenous addition of proteotoxic A4V SOD1. In the present in vivo study, we evaluated the pharmacological potential of a synthesized Au-PEG nanoconjugate in transgenic SOD1^G93A mice. We found differences in the detection of the onset of symptoms and the progression of the disease upon Au-PEG treatment when assessed using behavioral tests, such as rotarod and walking tests. Additionally, the gastrocnemius muscle histopathology showed notable alteration upon Au-PEG administration. The therapeutic potential of the nanoconjugate was found to be notable, with additional survival for ∼1 week, a delayed mean age at onset, and improved rotarod performance. Furthermore, molecular docking studies reveal that the addition of the lethal A4V SOD1 mutant to the tubulin dimer has a negative impact on the binding of the kinesin motor to tubulin (K_d = 1.4 × 10⁻⁷ mol L⁻¹vs. K_d = 2.5 × 10⁻⁹ mol L⁻¹), whereas the exogenous addition of gold nanoparticles (Au NPs) to the protein complex of A4V SOD1–tubulin has a substantially positive effect on the binding affinity of kinesin to the tubulin dimer (K_d = 2.7 × 10⁻¹² mol L⁻¹), reinstating the dynamics as a result. Thus, the engineering of self-therapeutic gold nanoparticles for combinatorial therapy holds potential and, therefore, the role of Au NPs in modifying the state of ALS deserves further investigation, with the eventual aim of managing the complex disease ALS.