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Loss of p21-activated kinase Mbt/PAK4 causes Parkinson-like phenotypes in Drosophila
- Source :
- Disease Models & Mechanisms, Vol 14, Iss 6 (2021)
- Publication Year :
- 2021
- Publisher :
- The Company of Biologists, 2021.
-
Abstract
- 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.
Details
- Language :
- English
- ISSN :
- 17548403, 17548411, and 54764319
- Volume :
- 14
- Issue :
- 6
- Database :
- Directory of Open Access Journals
- Journal :
- Disease Models & Mechanisms
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.6f041e164fc40cc909d83b547643197
- Document Type :
- article
- Full Text :
- https://doi.org/10.1242/dmm.047811