Abstract
SummaryDopaminergic (DA) neurons have been implicated as key targets in neurological disorders, notably those involving locomotor impairment, and are considered to be highly vulnerable to mitochondrial dysfunction, a common feature of such diseases. Here we investigated a Drosophila model of locomotor disorders in which functional impairment is brought about by pan-neuronal RNAi knockdown of subunit COX7A of cytochrome oxidase (COX). Despite minimal neuronal loss by apoptosis, the expression and activity of tyrosine hydroxylase was decreased by half. Surprisingly, COX7A knockdown specifically targeted to DA neurons did not produce locomotor defect. Instead, using various drivers, we found that COX7A knockdown in specific groups of cholinergic and glutamatergic neurons underlay the phenotype. Based on our main finding, the vulnerability of DA neurons to mitochondrial dysfunction as a cause of impaired locomotion in other organisms, including mammals, warrants detailed investigation.
Highlights
Mitochondrial stress, whether resulting from impaired respiration, oxidative damage, or defective protein quality control, has been proposed as a major underlying process in neurological diseases, notably those where locomotion is impaired, such as Parkinson’s disease (PD; recently reviewed by Ge et al, 2020)
SUMMARY Dopaminergic (DA) neurons have been implicated as key targets in neurological disorders, notably those involving locomotor impairment, and are considered to be highly vulnerable to mitochondrial dysfunction, a common feature of such diseases
Despite minimal neuronal loss by apoptosis, the expression and activity of tyrosine hydroxylase was decreased by half
Summary
Mitochondrial stress, whether resulting from impaired respiration, oxidative damage, or defective protein quality control, has been proposed as a major underlying process in neurological diseases, notably those where locomotion is impaired, such as Parkinson’s disease (PD; recently reviewed by Ge et al, 2020). DA neurons in Drosophila have been implicated in a number of behavioral processes, including feeding, sleep, and locomotion, and fly models of locomotor dysfunction strongly support a role for mitochondrial stress in the phenotype. In the Drosophila brain there are rather few DA neurons, mostly located in anatomically distinct clusters specified during embryogenesis (Hartenstein et al, 2017) Because of their functional and anatomical similarities with DA neurons in vertebrates, they are of great interest in the fields of neurodegeneration and other neurological disorders, both movement related and psychiatric (White et al, 2010). Prominent among them is the negative geotaxis (climbing) assay, which has been widely used to measure locomotor competence in adults It is frequently considered a marker for neurodegeneration, especially when used to score the effects of manipulating genes implicated in human neurodegenerative disease (Fernius et al, 2017). These include, for example, the Alzheimer-associated beta-amyloid peptide (Marcora et al, 2014), the familial PD gene Pink (Guo, 2012), or the Drosophila homologue of FUS (cabeza), implicated in one form of ALS (Frickenhaus et al, 2015)
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