Autophagy gridlock in tauopathy

Tauopathies are a group of neurodegenerative diseases characterized by the presence of intracellular aggregates containing the microtubule associated protein tau. Bulk degradation of aggregation-prone proteins can occur via autophagy. Here, we utilized the previously developed model of human tauopathy in Drosophila to examine how autophagy modulates human tau toxicity and to study the effects of human tau on the autophagic machinery. We showed that caloric restriction and rapamycin feeding suppressed the human tau-induced toxic phenotype, with a decrease in the soluble levels of human tau. Genetic upregulation of the autophagy/lysosomal system also alleviated human tau toxicity, whereas its downregulation exerted the opposite effect. We also showed that human tau misexpression induced the accumulation of autophagic intermediates which was correlated with a slight increase in macroautophagy induction. The autophagic intermediates were immunoreactive for Blue Cheese, the fly homolog of autophagy-linked FYVE protein, ALFY. A blockage in autophagic flux also contributed to the accumulation of autophagic intermediates with subsequent formation of large spherical bodies, which we termed giant autophagic bodies (GAB). In contrast to mature autolysosomes, GAB were significantly larger in size, higher in pH and contained a mixture of digested and undigested material indicating a blockage in the degradative capacity of macroautophagy. We demonstrated that lowering basal autophagy levels reduced the number of GAB. On the other hand, augmenting autophagy resulted in the formation of large autophagic intermediates that were poorly acidified and caused a decrease in the number of mature autolysosomes, implying an autophagy gridlock preventing the maturation of autophagic intermediates. Collectively, these results show that human tau misexpression both impaired and its toxicity was regulated by autophagy. Early activation of autpophagy suppressed tauopathy, likely through sequestration of soluble human tau; however, tauopathy also appeared to be associated with a gridlock in autophagic flux leading to the formation of large and poorly acidified autophagic intermediates.

Name thesis:degree_name

Neuroscience (Doctoral)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Neuroscience

Grantor

The University of Texas Medical Branch at Galveston

Author dc:creator

• Bakhoum, Mathieu 1985-

Advisor dc:contributor.advisor

• Jackson, George R

Committee members dc:contributor.committeemember

• Yamamoto, Ai
• Sherwood, Edward
• Neugebauer, Volker
• Carlton, Susan M
• Wairkar, Yogesh

• autophagy
• tau
• human tauopathies
• neurodegeneration
• Alzheimer Disease
• Giant autophagic bodies
• GAB
• Drosophila.

Handle dc:identifier.uri

http://hdl.handle.net/2152.3/827

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/827