Wnt/Fzd dysregulations in Amyotrophic Lateral Sclerosis: experimental and computational insights

Wingless-related integration site (Wnt) ligands are a conserved family of post-transcriptionally modified secreted proteins orchestrating fundamental processes as proliferation, self-renewing, phenotype determination, development, homeostasis, and repair. They bind to and activate Frizzled (Fzd) receptors/co-receptors families. Wnt/Fzd molecules are shared from embryonal to adult states in a plethora of different organisms and pathological conditions including amyotrophic lateral sclerosis (ALS). ALS is a neurodegenerative/neuroinflammatory disease caused by complex gene/environment interactions and distinguished by relentless collapse of upper/lower motor neurons, interruption of neuron-muscle communication, and muscle atrophy, culminating into irreversible paralysis and breathing failure. The mechanistic evolution of ALS is still poorly understood. Here, we provide updated experimental evidence about the crucial role that Wnt/Fzd modulations play in ALS, moreover describing some analytical frameworks tailored to investigate the pathological Wnt/Fzd signaling. We bridge transcriptomic, genomic, epigenomic data with bioinformatics, correlation/network analysis, and systems biology approaches, in order to advance some currently fragmented observations into more coherent and robust strategies dissecting the impact of Wnt/Fzd axis in ALS. Keeping an open mind on this scenario will stimulate future research directions and opportunities for ALS therapy.