A Conserved Role for p48 Homologs in Protecting Dopaminergic Neurons from Oxidative Stress

Abstract

Parkinson's disease (PD) is the most common neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Both environmental and genetic factors are thought to contribute to the pathogenesis of PD. Although several genes linked to rare familial PD have been identified, endogenous risk factors for sporadic PD, which account for the majority of PD cases, remain largely unknown. Genome-wide association studies have identified many single nucleotide polymorphisms associated with sporadic PD in neurodevelopmental genes including the transcription factor p48/ptf1a. Here we investigate whether p48 plays a role in the survival of DA neurons in Drosophila melanogaster and Caenorhabditis elegans. We show that a Drosophila p48 homolog, 48-related-2 (Fer2), is expressed in and required for the development and survival of DA neurons in the protocerebral anterior medial (PAM) cluster. Loss of Fer2 expression in adulthood causes progressive PAM neuron degeneration in aging flies along with mitochondrial dysfunction and elevated reactive oxygen species (ROS) production, leading to the progressive locomotor deficits. The oxidative stress challenge upregulates Fer2 expression and exacerbates the PAM neuron degeneration in Fer2 loss-of-function mutants. hlh-13, the worm homolog of p48, is also expressed in DA neurons. Unlike the fly counterpart, hlh-13 loss-of-function does not impair development or survival of DA neurons under normal growth conditions. Yet, similar to Fer2, hlh-13 expression is upregulated upon an acute oxidative challenge and is required for the survival of DA neurons under oxidative stress in adult worms. Taken together, our results indicate that p48 homologs share a role in protecting DA neurons from oxidative stress and degeneration, and suggest that loss-of-function of p48 homologs in flies and worms provides novel tools to study gene-environmental interactions affecting DA neuron survival.

Auxilin Underlies Progressive Locomotor Deficits and Dopaminergic Neuron Loss in a Drosophila Model of Parkinson’s Disease

“…During PD pathology, DA neuron death has been suggested to precede and underlie behavioral deficits. In addition to the PPM1/2 cluster, the PAM cluster has been shown to express the Drosophila p48 homolog 48-related-2 (Fer2) to protect DA neurons from oxidative stress and control locomotor activity (Bou Dib et al, 2014). Moreover, cells in the PAM cluster have been mapped to target the horizontal b' lobes of the MB for controlling locomotion (Riemensperger et al, 2013).…”

Drosophila Models of Sporadic Parkinson’s Disease

“…1), whose individual roles and connectivity are unfolding [16,17]. Startle-induced climbing assay and its variations (such as startle-induced negative geotaxis; SING) are the most commonly used methods to quantify fly's locomotor behavior in comparing organismal phenotypes of flies and human movement disorders [18][19][20][21]. These assays are distinct from recording the natural tendency to climb, known as negative geotaxis, but monitor the rate of climbing response of flies when knocked down to the bottom of a cylinder.…”

“…The climbing response is normally rapid, and failure to recover from the "shock" of being knocked-down suggest some defects in the functioning of nervous system in controlling initiation. Noteworthy, recent studies have demonstrated that at least a subset of DA neurons in the protocerebral anterior medial (PAM) cluster has important roles in the climbing response, much like DA neurons in mammalian SNpc, making flies ever relevant model system for the study of PD [18,22,23]. Figure 1.…”

“…Both p48/ptf1a and Ferd3l are involved in the control of neuronal development [166][167][168]. In the fly brain Fer2 is expressed in a limited number of neurons, including a subgroup of circadian pacemaker neurons [169][170][171] and two subclasses of DA neurons, PAM and PAL [18,172]. Intriguingly hypomorphic mutants of Fer2 exhibit PD-like phenotypes typical for fly models of PD.…”

“…Furthermore, it was also shown that oxidative stress elicited by the oxidants H2O2 or paraquat induces DA neuron loss specifically in the PAM neurons in Fer2 mutant flies. At the cellular levels, Fer2 mutation causes abnormality in the mitochondrial morphology and autophagosome formation, the well-known pathogenic molecular events implicated in PD, suggesting that Fer2 controls the expression of genes involved in multiple mechanisms that are normally protective of DA neurons [18,173]. Collectively, these results suggest that Fer2 mutant flies are useful for investigating mechanisms of DA neuron demise, especially the gene-environmental interaction with the presence of oxidative stress, thereby providing an opportunity to study pathogenic processes in PD.…”