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Abstract

The accumulation of dysfunctional or damaged mitochondria in neurons has been linked to the pathogenesis of many neurodegenerative diseases, including Parkinson’s disease. It has been proposed that the Parkinson’s-related proteins PINK1 and Parkin regulate mitochondrial quality control by selectively targeting depolarized mitochondria for autophagic degradation, a process known as mitophagy. The compartmentalization of mitochondrial turnover in neurons still remains unclear, but evidence suggests that mitochondria are locally degraded in the distal axon and perhaps in the neuromuscular junctions (NMJs). To study this, intact Drosophila nervous systems were analyzed in vivo by performing gentle dissections on third instar larvae to expose the ventral ganglia and segmental nerves with their NMJs. Both control larvae and parkin mutants (parkin25) were genetically modified to mark mitochondria via mitoGFP expression in their motor neurons, with park25 being additionally modified by deletion of the parkin gene. The physiological states of mitochondria were quantified through measurements of mitochondrial membrane potential, and the density of mitochondria in NMJs were analyzed through comparing αHRP and mitoGFP stain intensities in synaptic boutons. Unexpectedly, parkin25 mitochondria displayed normal readings in NMJs, indicating that mutant nerve terminals do not accumulate senescent mitochondria. In addition, reduced mitochondrial density was observed in synaptpark25ic boutons of parkin25 animals. These results argue against the hypothesis that loss of Parkin results in the accumulation of depolarized mitochondria, instead suggesting a reduction of organelle density in synaptic boutons as a result of Parkin deficiency. By elucidating the role of Parkin in the synapse of neurons, the pathogenic mechanism of Parkinson’s and other neurodegenerative diseases will be better understood.

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