The downward spiral of tau and autolysosomes: a new hypothesis in neurodegeneration

Abstract

A growing body of research has connected autophagy to neurodegenerative diseases such as Alzheimer disease (AD). In autopsied AD brain, large multivesicular bodies accumulate in neurons. Knockout mice deficient for key autophagy genes demonstrate age-dependent neurodegeneration. Most neurodegenerative diseases are characterized by accumulation of insoluble protein species; the type of protein and the location of aggregates within the nervous system help to define the type of disorder. It has been hypothesized that the inability to degrade such aggregates is a major causative factor in neuronal dysfunction and eventual neuronal death. As neurons are postmitotic and thus cannot regenerate themselves, mechanisms of protein clearance have received much attention in the field. The function of the ubiquitin-proteasome system (UPS) is impaired in models of neurodegeneration, and overexpression of chaperone proteins, such as those in the HSP70 family, leads to beneficial effects in many models of proteinopathies. Recently, studies of the effects of autophagy as a clearance mechanism have uncovered compelling evidence that inducing autophagy can alleviate many pathogenic and behavioral symptoms in animal and cellular models of neurodegeneration.

Keywords: Alzheimer disease; Drosophila; MAPT/tau; microtubule; phosphorylation.

Figure 1. Several factors can contribute to reduced lysosomal and other protein degradation mechanisms. Once past a point of equilibrium, a positive feedback loop of MAPT accumulation and decreased autolysosome function is initiated that causes progressive worsening of reduced protein clearance and impaired axonal transport, which may explain several phenomena of neurodegenerative tauopathies. Hyperphosphorylation of MAPT and insoluble MAPT aggregation are by-products in this model that may further impair protein degradation processes or cause other deleterious effects.