Investigating the role of clock gene Period in safeguarding dopaminergic neurons
Description: Neurodegenerative disorders, primarily affecting the elderly, pose a significant global health challenge. Among these disorders, Parkinson's disease (PD) ranks as the second most prevalent, afflicting over 10 million people worldwide. PD manifests with a wide range of motor and non-motor symptoms and is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). The absence of disease-modifying treatments underscores the need for a better understanding of PD.The majority of PD cases are sporadic, originating from a complex interplay of genetic and environmental factors. Although these factors are diverse and remain largely unknown, the frequent association of sleep and circadian disturbances with PD has raised questions on whether circadian rhythm disruption may serve as a risk factor for PD. Recent findings of genetic variants in clock genes associated with an increased risk of PD in certain populations support this possibility. However, the precise causal relationship between the circadian clock and PD pathogenesis remains elusive.We have recently embarked on addressing this question using Drosophila, a model organism known for its exceptional genetic tractability and its fundamental properties of the nervous system that closely resemble those in mammals. Our research has demonstrated that the Drosophila period gene (per), an essential component of the circadian clock, plays a pivotal role in preserving DA neurons. By controlling circadian rhythms, PER rhythmically gates the vulnerability of brain DA neurons to oxidative stress-induced degeneration. Moreover, the loss of PER induces age-dependent degeneration of DA neurons and exacerbates the susceptibility of DA neurons to oxidative stress-induced degeneration.Considering the high conservation of circadian clock machinery and mechanisms of neurodegeneration, our findings led us to hypothesize that mammalian PER proteins similarly contribute to the maintenance of DA neurons, aligning with genetic data from human populations. This research, using both Drosophila and mice, tests this hypothesis and seeks to uncover evolutionarily conserved mechanisms through which PER proteins safeguard DA neurons at the molecular, neuronal, and systemic levels. Given the multifactorial nature of PD etiology, we will also investigate functional interactions between PER and other chemical and genetic risk factors for dopaminergic neurodegeneration. Our findings will therefore not only illuminate the functions of PER homologs but also place them within a broader context. Specifically, we will pursue three independent but interconnected Aims that are built upon our previous findings and preliminary data:1. Identify subtypes of DA neurons susceptible to per null mutation and other risk factors, and elucidate the molecular and neural mechanisms underpinning the selective vulnerability in Drosophila.2. Investigate the role of the innate immune system in PD-related features in per mutant and other PD model flies.3. Elucidate the role of mammalian PER homologs in dopaminergic neurodegeneration.The outcomes of this research will hold significant implications for unraveling the pathogenesis of PD and shed light on the longstanding questions regarding the potential links between circadian dysfunction in PD. Ultimately, our research has the potential to pave the way for the development of effective therapeutic strategies and diagnostic tools for PD.
Amount: CHF 600,000
Funding type: research
Funder scheme: Project funding
Start date: 2024-07-01
End date: 2028-06-30
Investigator: Nagoshi, Emi
Institution: University of Geneva – GE
Funded outputs count: 2
Funder award ID: 10000329
OpenAlex ID: G729967310