davunetide and Mitochondrial-Diseases

In Parkinson's disease mitochondrial dysfunction can lead to a deficient ATP supply to microtubule protein motors leading to mitochondrial axonal transport disruption. Compromised axonal transport will then lead to a disorganized distribution of mitochondria and other organelles in the cell, as well as, the accumulation of aggregated proteins like alpha-synuclein. Moreover, axonal transport disruption can trigger synaptic accumulation of autophagosomes packed with damaged mitochondria and protein aggregates promoting synaptic failure. We previously observed that neuronal-like cells with an inherent mitochondrial impairment derived from PD patients contain a disorganized microtubule network, as well as, alpha-synuclein oligomer accumulation. In this work we provide new evidence that an agent that promotes microtubule network assembly, NAP (davunetide), improves microtubule-dependent traffic, restores the autophagic flux and potentiates autophagosome-lysosome fusion leading to autophagic vacuole clearance in Parkinson's disease cells. Moreover, NAP is capable of efficiently reducing alpha-synuclein oligomer content and its sequestration by the mitochondria. Most interestingly, NAP decreases mitochondrial ubiquitination levels, as well as, increases mitochondrial membrane potential indicating a rescue in mitochondrial function. Overall, we demonstrate that by improving microtubule-mediated traffic, we can avoid mitochondrial-induced damage and thus recover cell homeostasis. These results prove that NAP may be a promising therapeutic lead candidate for neurodegenerative diseases that involve axonal transport failure and mitochondrial impairment as hallmarks, like Parkinson's disease and related disorders.

Topics: Aged; alpha-Synuclein; Autophagy; Case-Control Studies; Cell Line; Female; Humans; Lysosomes; Male; Membrane Potential, Mitochondrial; Microtubules; Middle Aged; Mitochondria; Mitochondrial Diseases; Neurons; Neuroprotective Agents; Oligopeptides; Parkinson Disease; Ubiquitination; Vacuoles

The peptide NAP (NAPVSIPQ) was shown to protect neurons against a wide variety of insults. Particularly, NAP was shown to be neuroprotective in vitro against cyanide in hippocampal cultures and against oxygen-glucose deprivation in hippocampal and cortical neuronal cultures. Cyanide causes energy depletion in the cell and destroys the cytoskeleton, and NAP has been shown before to protect the microtubule cytoskeleton. The current study explored the effect of NAP on cyanide-induced microtubule destruction in cerebral cortical cultures. Sodium cyanide (6.8 mM) reduced the number of neurons containing intact microtubules as identified by bIII-tubulin immunostaining. When sodium cyanide was added together with NAP (10(-14)-10(-12) M), complete protection was observed. Although the primary site of action of cyanide is considered to be the mitochondria, the current results involve microtubule destruction by cyanide toxicity that is completely reversed by NAP treatment.

Topics: Animals; Cells, Cultured; Cyanides; Microtubules; Mitochondrial Diseases; Nerve Degeneration; Neurons; Neuroprotective Agents; Oligopeptides; Rats; Rats, Sprague-Dawley; tau Proteins