Exploring the link between Parkinson's disease and type 2 diabetes mellitus in Drosophila

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease. Diabetes mellitus (DM) is a metabolic disease characterized by high levels of glucose in blood. Recent epidemiological studies have highlighted the link between both diseases; it is even considered that DM might be a risk factor for PD. To further investigate the likely relation of these diseases, we have used a Drosophila PD model based on inactivation of the DJ‐1β gene (ortholog of human DJ‐1), and diet‐induced Drosophila and mouse type 2 DM (T2DM) models, together with human neuron‐like cells. T2DM models were obtained by feeding flies with a high sugar‐containing medium, and mice with a high fat diet. Our results showed that both fly models exhibit common phenotypes such as alterations in carbohydrate homeostasis, mitochondrial dysfunction or motor defects, among others. In addition, we demonstrated that T2DM might be a risk factor of developing PD since our diet‐induced fly and mouse T2DM models present DA neuron dysfunction, a hallmark of PD. We also confirmed that neurodegeneration is caused by increased glucose levels, which has detrimental effects in human neuron‐like cells by triggering apoptosis and leading to cell death. Besides, the observed phenotypes were exacerbated in DJ‐1β mutants cultured in the high sugar medium, indicating that DJ‐1 might have a role in carbohydrate homeostasis. Finally, we have confirmed that metformin, an antidiabetic drug, is a potential candidate for PD treatment and that it could prevent PD onset in T2DM model flies. This result supports antidiabetic compounds as promising PD therapeutics.

Evaluation of type 1 diabetes mellitus as a risk factor of Parkinson's disease in a Drosophila model

“…They also showed DA neurodegeneration, a result validated in a T2DM mice model (Sanz et al, 2022). Overall, these results allowed us to confirm the link between both diseases.…”

“…Levels of glycogen and soluble carbohydrates in 15-day-old female flies of each genotype were calculated by using the anthrone reagent as previously described in Sanz et al (2022). All experiments were carried out using three biological replicates and three technical replicates for each sample.…”

“…Protein extracts were obtained from fly heads of 15-day-old females of each genotype. Western blots were performed as described in Sanz et al (2022). Primary antibodies used were anti-tyrosine hydroxylase (TH) (1:1000, Sigma; #AB152) and anti-α-tubulin (1:5000; Hybridoma Bank; #12G10).…”

Plantamajoside Alleviates Substantia Nigra Damage in Parkinson’s Disease Mice by Inhibiting HDAC2/MAPK Signaling and Reducing Microglia Polarization

“…Previous studies have demonstrated that the pathogenesis of PD is related to aging factors, environmental factors, genetic factors, oxidative stress, free radical formation, and associated nerve inflammation, but recent evidence suggests that chronic nerve inflammation caused by microglia activation may be important in the degenerative process. 6,7 Activated microglia are a major factor in neuroinflammation and dopaminergic neurodegeneration. 8,9 Overactivation of microglia results in the release of several neurotoxic factors, which contributes to the process of dopaminergic neurodegeneration.…”

“…Parkinson’s disease (PD) is known as a common neurodegenerative disease with major clinical manifestations of motor dysfunction, such as cognitive impairment. , PD usually occurs in people with the age of over 65 and is caused by the progressive degeneration of dopaminergic neurons in the substantia nigra (SN). − The cause of PD is still elusive. Previous studies have demonstrated that the pathogenesis of PD is related to aging factors, environmental factors, genetic factors, oxidative stress, free radical formation, and associated nerve inflammation, but recent evidence suggests that chronic nerve inflammation caused by microglia activation may be important in the degenerative process. , Activated microglia are a major factor in neuroinflammation and dopaminergic neurodegeneration. , Overactivation of microglia results in the release of several neurotoxic factors, which contributes to the process of dopaminergic neurodegeneration. , Therefore, inhibition of microglial activation may contribute to the treatment and prevention of PD. In addition, finding more drugs is needed to combat this disease.…”