Rab11 rescues muscle degeneration and synaptic morphology in the park13/+ Parkinson model of Drosophila melanogaster

Abstract

Mutation in parkin and pink1 is associated with Parkinson's disease (PD), the most common movement disorder characterized by muscular dysfunction. In a previous study, we observed that Rab11, a member of the small Ras GTPase family, regulates the mitophagy pathway mediated by Parkin and Pink1 in the larval brain of the Drosophila PD model. Here, we describe that the expression and interaction of Rab11 in the PD model of Drosophila is highly conserved across different phylogenic groups. The loss of function in these two proteins, i.e., Parkin and Pink1, leads to mitochondrial aggregation. Rab11 loss of function results in muscle degeneration, movement disorder and synaptic morphological defects. We report that overexpression of Rab11 in park¹³ heterozygous mutant improves muscle and synaptic organization by reducing mitochondrial aggregations and improving cytoskeleton structural organization. We also show the functional relationship between Rab11 and Brp, apre-synaptic scaffolding protein, required for synaptic neurotransmission. Using park¹³ heterozygous mutant and pink1RNAi lines, we showed reduced expression of Brp and consequently, there were synaptic dysfunctions including impaired synaptic transmission, decreased bouton size, increase in the bouton numbers, and the length of axonal innervations at the larval neuromuscular junction (NMJ). These synaptic alterations were rescued with the over-expression of Rab11 in the park¹³ heterozygous mutants. In conclusion, this work emphasizes the importance of Rab11 in rescuing muscle degeneration, movement dysfunction and synaptic morphology by preserving mitochondrial function in the PD model of Drosophila.

Keywords: Drosophila; Indirect flight muscle (IFM); Mitochondria; Movement disorder; Muscular degeneration; Neuromuscular junction; Parkinson’s disease; Rab11.