Abstract
ABSTRACTMiro (mitochondrial Rho GTPases), a mitochondrial outer membrane protein, facilitates mitochondrial axonal transport along the microtubules to facilitate neuronal function. It plays an important role in regulating mitochondrial dynamics (fusion and fission) and cellular energy generation. Thus, Miro might be associated with the key pathologies of several neurodegenerative diseases (NDs) including Alzheimer's disease (AD). In the present manuscript, we have demonstrated the possible genetic interaction between Miro and AD-related genes such as Tau, Aβ42 and Appl in Drosophila melanogaster. Ectopic expression of Tau, Aβ42 and Appl induced a rough eye phenotype, defects in phototaxis and climbing activity, and shortened lifespan in the flies. In our study, we have observed that overexpression of Miro improves the rough eye phenotype, behavioral activities (climbing and phototaxis) and ATP level in AD model flies. Further, the improvement examined in AD-related phenotypes was correlated with decreased oxidative stress, cell death and neurodegeneration in Miro overexpressing AD model flies. Thus, the obtained results suggested that Miro genetically interacts with AD-related genes in Drosophila and has the potential to be used as a therapeutic target for the design of therapeutic strategies for NDs.This article has an associated First Person interview with the first author of the paper.
Highlights
Mitochondrial Rho GTPase (Miro) is an evolutionary conserved mitochondrial outer membrane protein that plays a pivotal role in mitochondrial axonal transport and maintenance of mitochondrial dynamics (Kay et al, 2018; Lee and Lu, 2014; Reis et al, 2009; Tang, 2016)
Several studies have suggested that overexpression of Alzheimer’s disease (AD)-related genes (Appl, Amyloid Beta 42 (Aβ42) and Tau) in Drosophila induced caspase-depended cell death via increasing the cellular stress and mitochondrial dysfunction resulting in reduced Adenosine triphosphate (ATP) level and enhanced oxidative stress (Cai et al, 2005; Pérez et al, 2018; Park et al, 2013)
Miro plays a key role in neurodegeneration by regulating the mitochondrial axonal transport but the molecular details of how Miro interacts with AD-related genes (Tau, Aβ42 and Amyloid Precursor Protein like (Appl)) are not well understood yet
Summary
Mitochondrial Rho GTPase (Miro) is an evolutionary conserved mitochondrial outer membrane protein that plays a pivotal role in mitochondrial axonal transport and maintenance of mitochondrial dynamics (fusion and fission) (Kay et al, 2018; Lee and Lu, 2014; Reis et al, 2009; Tang, 2016). A study by Iijima-Ando and Iijima, (2010) have shown that overexpression of Aβ42 in AD model flies results in the reduction of mitochondria numbers in axons and dendrites and increases mitochondria accumulation in somata of the neurons This mitochondrial mislocalization exacerbated by Miro mutation enhances Aβ42-induced behavioral deficits in Drosophila. The Drosophila mitochondrial axonal transport protein complex Miro/Milton/kinesin is homologous to mammalian Miro/TRAK/KIF5 protein complex (Lee and Lu, 2014; Tang, 2016) These similarities between Drosophila and human mitochondrial axonal transport proteins make Drosophila a powerful model organism to study the mitochondria dysfunction related pathologies in AD (Kay et al, 2018; Russo et al, 2009). In the current study, we have studied the possible genetic interaction between the mitochondrial axonal transport gene Miro and AD-related genes (Tau, Aβ42 and Appl) in Drosophila
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