Mutant A53T alpha-synuclein induces neuronal death by increasing mitochondrial autophagy.
Parkinson disease is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. α-Synuclein accumulation in turn leads to compensatory effects that may include the up-regulation of autophagy. Another common feature of Parkinson disease (PD) is mitochondrial dysfunction. Here, we provide evidence that the overactivation of autophagy may be a link that connects the intracellular accumulation of α-synuclein with mitochondrial dysfunction. We found that the activation of macroautophagy in primary cortical neurons that overexpress mutant A53T α-synuclein leads to massive mitochondrial destruction and loss, which is associated with a bioenergetic deficit and neuronal degeneration. No mitochondrial removal or net loss was observed when we suppressed the targeting of mitochondria to autophagosomes by silencing Parkin, overexpressing wild-type Mitofusin 2 and dominant negative Dynamin-related protein 1 or blocking autophagy by silencing autophagy-related genes. The inhibition of targeting mitochondria to autophagosomes or autophagy was also partially protective against mutant A53T α-synuclein-induced neuronal cell death. These data suggest that overactivated mitochondrial removal could be one of the contributing factors that leads to the mitochondrial loss observed in PD models.
Department of Pharmacology, University of Tartu, Ravila 19, 51014 Tartu, Estonia.
Vinay
V
Choubey
Dzhamilja
D
Safiulina
Annika
A
Vaarmann
Michal
M
Cagalinec
Przemyslaw
P
Wareski
Malle
M
Kuum
Alexander
A
Zharkovsky
Allen
A
Kaasik
D019943:Amino Acid Substitution; D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D020558:GTP Phosphohydrolases; D020868:Gene Silencing; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat
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