The rescue of microtubule-dependent traffic recovers mitochondrial function in Parkinson's disease

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1842

Article

Esteves, A. R.¹  Gozes, I.²  Cardoso, S. M.^1,3 

[1] Univ Coimbra, CNC Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal

[2] Tel Aviv Univ, Sackler Fac Med, Dept Human Mol Genet & Biochem, Sagol Sch Neurosci,Adams Super Ctr Brain Studies, IL-69978 Tel Aviv, Israel

[3] Univ Coimbra, Fac Med, P-3004517 Coimbra, Portugal

关键词: NAP;    Mitochondria dynamics;    Microtubule network;   

DOI  :  10.1016/j.bbadis.2013.10.003

来源: Elsevier

【 摘 要 】

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-synudein 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. (C) 2013 Elsevier B.V. All rights reserved.

【 授权许可】

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