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

Abstract

Parkinson's disease (PD) provokes bradykinesia, resting tremor, rigidity and postural instability but 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 PAK4 with PD, leaving open the question of a causative relationship of mutations in this gene for manifestation of PD symptoms. To figure out 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 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 life span. We conclude that mutations in Mbt/PAK4 can play a causative role in the development of Parkinson's disease phenotypes.

Metabolic and neurobehavioral disturbances induced by purine recycling deficiency inDrosophila

“…The fact that rescue was not complete could be due to a dominant negative effect of the mutation, as suggested by enzymatic assays on extracts of heterozygous Aprt 5 mutants (Figure S4). Previous work from our and other laboratories showed that DA neurons control the SING behavior in Drosophila (Feany and Bender 2000; Friggi-Grelin et al 2003; Riemensperger et al 2011; Vaccaro et al 2017; Sun et al 2018) and that PAM DA neuron degeneration induce SING defects in various Parkinson’s disease models (Riemensperger et al 2013; Bou Dib et al 2014; Tas et al 2018; Pütz et al 2021). Here, we found that knocking down Aprt either in all DA neurons or only in the PAM DA neurons was sufficient to induce early SING defects.…”

The utility and caveat of split-GAL4s in the study of neurodegeneration

“…We and others have previously shown the loss of dopaminergic neurons (DA) within the protocerebral anterior medial (PAM) cluster by genetic or pharmacological insults in adult Drosophila brains [11,17–19]. Although the number of PAM neuron loss observed so far varies between 15% and 80%, other DA clusters remain unaffected.…”

“…Drosophila brains [11,[17][18][19]. Although the number of PAM neuron loss observed so far varies between 15% and 80%, other DA clusters remain unaffected.…”

Cracking the Code of Neuronal Cell Fate

“…The p21 activated kinase Pak4 plays a pivotal role in neuronal pathophysiology, promoting the activity of transcription factors involved in cell survival, such as Akt and Cepbp and, thus, contributing to a wide range of intracellular processes including cytoskeletal dynamics, neuronal development, axonal outgrowth and neuronal survival [ 49 , 50 , 51 ]. Down-regulated expression of Pak4 has been associated with neurodegenerative disorders, including Amyotrophic Lateral Sclerosis and Parkinson’s disease, and it has been proposed as a therapeutic target against cancer and neurodegeneration [ 52 , 53 , 54 , 55 ]. Nerve growth factor receptor Ntrk1 promotes neuronal survival, proliferation and differentiation in neuronal populations, representing a clinically relevant target in neurology [ 56 , 57 , 58 , 59 , 60 ].…”