Tau Ubiquitination, Degradation and Aggregation

The tau protein, which is a primary component of Alzheimer’s disease, has been recognized for several years as a substrate for ubiquitination, a process that targets abnormal proteins for degradation. More recently, impaired protein removal has emerged as a theme related to many neurodegenerative diseases that cause a variety of dementias; however, the relationship between impaired degradation of these protein aggregates and the clinical manifestation of the respective disorder remains unclear. Evidence implicating faulty protein ubiquitination and degradation in these disorders has primarily extended from the idea that the non-degraded protein aggregates implicated in disease onset impair/harm cells through a variety of mechanisms, from triggering cell death to sequestering vital proteins of the degradation pathway. Recent in vivo evidence, however, would argue that the cell death associated with Alzheimer’s disease is not necessarily due to tau aggregation, but rather these aggregates may be a method of last resort to protect neurons that are distressed for other reasons. We previously identified CHIP, as a tau ubiquitin ligase, which is involved in the recognition, ubiquitination and degradation of the tau protein. We have shown that CHIP deficiency in C. elegans and CHIP negative mice lead to a pathogenic conversion and accumulation of tau into a non-aggregated (soluble), ubiquitin-negative, hyper-phosphorylated species. CHIP negative mice also had increased apoptotic activity (programmed cell death), and smaller brain size compared to wildtype controls suggesting neuronal loss in these animals. Our observations demonstrate that CHIP is clearly involved in the ubiquitination and removal of pathogenic tau species and perhaps involved in the maturation of tau lesions.

Our goal is to:

1. Identity the specific modifications on tau itself that trigger its ubiquitination,
2. Identify those proteins involved in the pathway leading up to this process, and
3. Determine whether tau aggregation per se is the primary toxic event in Alzheimer’s disease progression or whether this is actually a protective mechanism carried out by the neuronal degradative machinery to maintain brain function for as long as possible.

The delineation of these processes represents an initial step toward understanding the role of tau ubiquitination in the pathogenesis of Alzheimer's disease and other neurodegenerative diseases.