The shift to a proteinopenia paradigm in neurodegeneration

The toxic proteinopathy paradigm has defined neurodegenerative disorders for over a century. This gain-of-function (GOF) framework posited that proteins become toxic when turned into amyloids (pathology), predicting that lowering its levels would translate into clinical benefits. Genetic observations used to support a GOF framework are equally compatible with a loss-of-function (LOF) framework, as the soluble pool of proteins rendered unstable by these mutations (e.g., APP in Alzheimer's disease, SNCA in Parkinson's disease) aggregate, becoming depleted. In this review, we highlight misconceptions that have prevented LOF from gaining currency. Some of these misconceptions include no phenotype in knock-out animals (there is neurodegenerative phenotype in knock-out animals) and high levels of proteins in patients (patients have lower levels of the proteins involved in neurodegeneration than healthy age-matched controls). We also expose the internal contradictions within the GOF framework, namely that (1) pathology can have both pathogenic and protective roles; (2) the neuropathology gold standard for diagnosis can be present in normal individuals and absent in those affected; (3) oligomers are the toxic species even if they are ephemeral and decrease over time. We therefore advocate for a paradigm shift from proteinopathy (GOF) to proteinopenia (LOF) based on the universal depletion of soluble functional proteins in neurodegenerative diseases (low amyloid-β 42 in Alzheimer's disease, low α-synuclein in Parkinson's disease, and low tau in progressive supranuclear palsy) and supported by the confluence of biologic, thermodynamic, and evolutionary principles with proteins having evolved to perform a function, not to become toxic, and where protein depletion is consequential. Such shift to a Proteinopenia paradigm is necessary to examining the safety and efficacy of protein replacement strategies instead of perpetuating a therapeutic paradigm with further antiprotein permutations.