Abstract
ABSTRACTParkinson's disease (PD) provokes bradykinesia, resting tremor, rigidity and postural instability, and also non-motor symptoms such as depression, anxiety, sleep and cognitive impairments. Similar phenotypes can be induced in Drosophila melanogaster through modification of PD-relevant genes or the administration of PD-inducing toxins. Recent studies correlated deregulation of human p21-activated kinase 4 (PAK4) with PD, leaving open the question of a causative relationship of mutations in this gene for manifestation of PD symptoms. To determine whether flies lacking the PAK4 homolog Mushroom bodies tiny (Mbt) show PD-like phenotypes, we tested for a variety of PD criteria. Here, we demonstrate that mbt mutant flies show PD-like phenotypes including age-dependent movement deficits, reduced life expectancy and fragmented sleep. They also react to a stressful situation with higher immobility, indicating an influence of Mbt on emotional behavior. Loss of Mbt function has a negative effect on the number of dopaminergic protocerebral anterior medial (PAM) neurons, most likely caused by a proliferation defect of neural progenitors. The age-dependent movement deficits are not accompanied by a corresponding further loss of PAM neurons. Previous studies highlighted the importance of a small PAM subgroup for age-dependent PD motor impairments. We show that impaired motor skills are caused by a lack of Mbt in this PAM subgroup. In addition, a broader re-expression of Mbt in PAM neurons improves life expectancy. Conversely, selective Mbt knockout in the same cells shortens lifespan. We conclude that mutations in Mbt/PAK4 can play a causative role in the development of PD phenotypes.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disease and the most prevalent movement disorder
In this study, we demonstrated that, in the absence of Mushroom bodies tiny (Mbt), flies show a wide range of phenotypes related to PD
Loss of Mbt function has a negative effect on the number of DA protocerebral anterior medial (PAM) neurons (Fig. 6A) as part of the neural circuity controlling motor behavior
Summary
Parkinson’s disease (PD) is a common neurodegenerative disease and the most prevalent movement disorder. PD is mainly characterized by motor symptoms such as bradykinesia, resting tremor, rigidity and postural instability, but is accompanied by non-motor symptoms including depression, anxiety, olfactory dysfunction, sleep disorders. To explain PD pathology, Braak and co-workers proposed a model in which Lewy bodies (aggregations of proteins including α-synuclein and ubiquitin) form and spread in the brain (Braak et al, 2003) This model only explains the symptoms of some PD variants (Obeso et al, 2010)
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