Loss of p21-activated kinase Mbt/PAK4 causes Parkinson-like phenotypes in Drosophila

Disease Models & Mechanisms

Thomas Raabe¹  Elisa Rauh¹  Sophie Kaiser¹  Stephanie M. Pütz¹  Jette Kram¹  Romy Toews¹  Yi Lueningschroer-Wang²  Dirk Rieger² 

[1] Medical Radiation and Cell Research, Biocenter, Am Hubland, University of Würzburg, D-97074 Würzburg, Germany;Neurobiology and Genetics, Biocenter, Am Hubland, University of Würzburg, D-97074 Würzburg, Germany;

关键词: drosophila;    parkinson's disease;    mbt;    pak4;    negative geotaxis;    sleep fragmentation;    life expectancy;    emotional behavior;    dopaminergic pam cluster neurons;   

DOI  :  10.1242/dmm.047811

来源: DOAJ

【 摘 要 】

Parkinson'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.

【 授权许可】

Unknown