Amyloid-ß-induced mitochondrial dysfunction impairs the autophagic lysosomal pathway in a tubulin dependent pathway.

Mitochondrial dysfunction is observed in Alzheimer's disease (AD) brain and peripheral tissues. Amyloid-ß (Aß) peptides are known to interact with several proteins inside the mitochondria, leading to mitochondrial dysfunction. Recent studies have provided substantial evidence that mitochondria serve as direct targets for Aß-mediated neuronal toxicity. The observations that Aß progressively accumulates in cortical mitochondria from AD patients and transgenic AD type mouse models suggest the role of mitochondrial Aß in the pathogenesis or development of AD. Herein, we studied the downstream signaling pathways induced by Aß-mediated mitochondrial metabolism alterations and its consequences on cellular fate. We found that Aß peptides induced an increase in NAD+levels and a decrease in ATP levels, which was related with decreases in acetylated tubulin levels and tau hyperphosphorylation. As a result of microtubule disruption, alterations in macroautophagy, like a decrease in autophagossome degradation and altered cellular distribution of LC3B, were found. Taxol, a microtubule stabilizer drug, was able to restore microtubule network and to prevent cell death induced by Aß peptides. Our data shows for the first time that mitochondrial and cytosolic Aß oligomers were significantly reduced upon microtubule dynamics re-establishment. These observations point out that an intervention at a microtubule level may be effective as a disease modifying therapy.

Therapeutic intervention at cellular quality control systems in Alzheimer's and Parkinson's diseases.

Cellular homeostasis relies on quality control systems so that damaged biologic structures are either repaired or degraded and entirely replaced by newly formed proteins or even organelles. The clearance of dysfunctional cellular structures in long-lived postmitotic cells, like neurons, is essential to eliminate, per example, defective mitochondria, lipofuscin-loaded lysosomes and oxidized proteins. Short-lived proteins are degraded mainly by proteases and proteasomes whether most long-lived proteins and all organelles are digested by autophagy in the lysosomes. Recently, it an interplay was established between the ubiquitin-proteasome system and macroautophagy, so that both degradative mechanisms compensate for each other. In this article we describe each of these clearance systems and their contribution to neuronal quality control. We will highlight some of the findings that provide evidence for the dysfunction of these systems in Alzheimer's and Parkinson's diseases. Ultimately, we provide an outline on potential therapeutic interventions based on the modulation of cellular degradative systems.

Cross-talk between mitochondria and proteasome in Parkinson's disease pathogenesis.

Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder, characterized by the selective loss of nigrostriatal dopaminergic neurons, and the presence of intracellular insoluble proteinaceous inclusions, known as Lewy Bodies. Although PD etiopathogenesis remains elusive, the leading hypothesis for the death of specific groups of neurons establishes that mitochondrial dysfunction, alterations in the ubiquitin-proteasomal system (UPS), and oxidative stress are major events that act synergistically causing this devastating disease. In this review we will focus on mitochondrial impairment and its implications on proteasomal function and alpha-synuclein aggregation. We will address the role of mitochondria and proteasome cross-talk in the neuronal loss that leads to PD and discuss how this knowledge might further improve patient therapy.