TY  - JOUR
A1  - Pütz, Stephanie M.
A1  - Kram, Jette
A1  - Rauh, Elisa
A1  - Kaiser, Sophie
A1  - Toews, Romy
A1  - Lueningschroer-Wang, Yi
A1  - Rieger, Dirk
A1  - Raabe, Thomas
T1  - Loss of p21-activated kinase Mbt/PAK4 causes Parkinson-like symptoms in Drosophila
JF  - Disease Models & Mechanisms
N2  - 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.
KW  - Sleep fragmentation
KW  - Life expectancy
KW  - Emotional behavior
KW  - Dopaminergic PAM cluster neurons
KW  - Drosophila
KW  - Parkinson's disease
KW  - Mbt
KW  - PAK4
KW  - Negative geotaxis
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259222
VL  - 14
IS  - 6
ER  -