The Neurobiology of Neurodegeneration
The reversible polymerization of proteins is a process necessary for life. In neurodegeneration, the abnormal and seemingly irreversible polymerization of several different abundant proteins in the brain pathologically defines disease into predictable stages. Linkage analyses and genome-wide associations prove that these proteins that form fibrils, oligomers, and other conformations are not mere bystanders in disease susceptibility but can drive neurodegeneration. Yet, inclusion abundance often poorly predicts clinical phenotypes, and mixed pathologies common in patients that involve several different proteins challenge therapeutics that directly target protein aggregation. Recent studies have nominated critical modulators of disease susceptibility and progression that include inflammation, microbiome, and the cell-to-cell propagation of abnormal proteins. Biomarkers that unravel disease heterogeneity to identify patients that might benefit most from targeting these critical modifiers promise to revolutionize bench-to-clinic approaches. With better precision in therapeutic strategies, it is hoped that the first wave of disease modifying drugs is already under development, with many more promising avenues yet to be explored.