Endosomal Trafficking as a Determinant of Selective Cellular Vulnerability in Alzheimer’s and Parkinson’s Diseases
Every major neurodegenerative disease has familial sub-types that are characterized by mutations in genes expressed in all cells in the body. Why, then, are only certain cell types vulnerable to them? Although one could argue in principle that neurons, being quiescent cells with long axons, may be inherently more sensitive to certain kinds of disturbances than cells in other tissues, that argument fails to explain why, for example, some alleles of the VPS35 gene cause Parkinson’s disease (death of dopaminergic neurons) while others cause Alzheimer’s disease (death of cortical neurons). It also fails to explain why Alzheimer’s disease always starts in the trans-entorhinal cortex and spread to the hippocampal formation and amygdala while Parkinson’s disease tends to start in the vagus nerve and spreads to the locus coeruleus and thence to the basal ganglia. My collaborator Scott Small (Columbia University School of Medicine) and I believe that endosomal protein trafficking provides a possible explanation. I will review what is known about such trafficking in neurons and how human genetics, cell biology and anatomical biology all integrate to link this pathway to both Alzheimer’s and Parkinson’s diseases, and how different disturbances of this pathway may account for the selective cellular vulnerabilities observed in these diseases, as well as their strong comorbidity.