Modulation of O-linked N-acetylglucosamine (O-GlcNAc) residues on proteins has emerged as a highly promising target for a range of neurodegenerative diseases. Extensive independent validation of this target using both chemical and genetic methods has been established. This conserved protein modification is found on nuclear and cytoplasmic proteins, including tau, TDP-43 and ɑ-synuclein. This reversible modification is regulated by two enzymes. O-GlcNAc transferase (OGT) installs O-GlcNAc whereas O-GlcNAcase (OGA) removes this modification. Elevated O-GlcNAc levels hinder pathogenic aggregation of proteins. For example, tau protein forms aggregates in Alzheimer’s disease (AD), which is prevented by tau O-GlcNAcylation. Alectos pioneered the development of potent OGA inhibitors that are highly active in brain. Inhibition of OGA in mouse AD models increases brain and tau O-GlcNAc levels, leading to reduced levels of aggregated tau and reduced neurodegeneration. In addition, inhibition of OGA also decreases aggregation of ɑ-synuclein protein, which is involved in Parkinson’s disease (PD), and TDP-43, which is involved in frontotemporal dementia (FTD) and ALS. Notably, recent studies in mouse PD models show that OGA inhibition reduces levels of ɑ-synuclein aggregates in brain and also reduces neurodegeneration. Alectos is developing novel OGA inhibitors as a disease-modifying strategy for AD, PD, FTD, and related diseases.