Using Graphene-Based Biosensors to Detect Dopamine for Efficient Parkinson’s Disease Diagnostics

Parkinson’s disease (PD) is a neurodegenerative disease in which the neurotransmitter dopamine (DA) depletes due to the progressive loss of nigrostriatal neurons. Therefore, DA measurement might be a useful diagnostic tool for targeting the early stages of PD, as well as helping to optimize DA replacement therapy. Moreover, DA sensing appears to be a useful analytical tool in complex biological systems in PD studies. To support the feasibility of this concept, this mini-review explores the currently developed graphene-based biosensors dedicated to DA detection. We discuss various graphene modifications designed for high-performance DA sensing electrodes alongside their analytical performances and interference studies, which we listed based on their limit of detection in biological samples. Moreover, graphene-based biosensors for optical DA detection are also presented herein. Regarding clinical relevance, we explored the development trends of graphene-based electrochemical sensing of DA as they relate to point-of-care testing suitable for the site-of-location diagnostics needed for personalized PD management. In this field, the biosensors are developed into smartphone-connected systems for intelligent disease management. However, we highlighted that the focus should be on the clinical utility rather than analytical and technical performance.

Are lysosomes potential therapeutic targets for Parkinson’s disease?

Background: Parkinson´s disease (PD) is the second most common neurodegenerative disorder, affecting 2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy bodies (LBs). Recently, genome-wide association studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. Aim: The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.

Effects of L-dopa on expression of prolactin and synaptotagmin IV in 17-estradiol-induced prolactinomas of ovariectomized hemiparkinsonian rats

Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. Dopamine precursor L-dopa is used as the first-line treatment for PD. Evidence suggests neuroprotective effects of estrogens in PD. Since both E2 and L-dopa act as regulators of prolactin secretion from the pituitary gland, we investigated their effect on the expression of prolactin (PRL) in prolactinomas that developed in ovariectomized hemiparkinsonian rats treated with 17b-estradiol (E2). We also investigated the effect of E2 and L-dopa on the expression of synaptotagmin IV (Syt IV), an immediate early gene whose product is abundant in the pituitary gland and was found to be highly co-expressed with PRL in lactotrophs (> 90%). The hemiparkinsonian rat model was obtained by unilateral lesioning of dopaminergic nigrostriatal neurons. Rats received silastic tubing implants with E2 and were treated with L-dopa. ELISA and immunohistochemistry were used to assess the serum concentrations of PRL and E2 and expression of PRL and SytIV in the tissue of adenohypophysis, respectively. We found that high levels of serum 17b-estradiol were associated with the upregulation of Syt IV and PRL in PRL-ir cells, while treatment with L-dopa decreased the size of prolactinomas and downregulated Syt IV but had no effect on PRL expression or serum concentrations.

Cyto/Biocompatibility of Dopamine Combined with the Antioxidant Grape Seed-Derived Polyphenol Compounds in Solid Lipid Nanoparticles

Background: The loss of nigrostriatal neurons containing dopamine (DA) together with the “mitochondrial dysfunction” in midbrain represent the two main causes related to the symptoms of Parkinson’s disease (PD). Hence, the aim of this investigation is to co-administer the missing DA and the antioxidant grape seed-derived proanthocyanidins (grape seed extract, GSE) in order to increase the levels of the neurotransmitter (which is unable to cross the Blood Brain Barrier) and reducing the oxidative stress (OS) related to PD, respectively. Methods: For this purpose, we chose Solid Lipid Nanoparticles (SLN), because they have been already proven to increase DA uptake in the brain. DA-SLN adsorbing GSE (GSE/DA-SLN) were formulated and subjected to physico-chemical characterization, and their cytocompatibility and protection against OS were examined. Results: GSE was found on SLN surface and release studies evidenced the efficiency of GSE in preventing DA autoxidation. Furthermore, SLN showed high mucoadhesive strength and were found not cytotoxic to both primary Olfactory Ensheathing and neuroblastoma SH-SY5Y cells by MTT test. Co-administration of GSE/DA-SLN and the OS-inducing neurotoxin 6-hydroxydopamine (100 μM) resulted in an increase of SH-SY5Y cell viability. Conclusions: Hence, SLN formulations containing DA and GSE may constitute interesting candidates for non-invasive nose-to-brain delivery.

Overexpression of Buffy enhances the loss of parkin and suppresses the loss of Pink1 phenotypes in Drosophila

Mutations in parkin (PARK2) and Pink1 (PARK6) are responsible for autosomal recessive forms of early onset Parkinson’s disease (PD). Attributed to the failure of neurons to clear dysfunctional mitochondria, loss of gene expression leads to loss of nigrostriatal neurons. The Pink1/parkin pathway plays a role in the quality control mechanism aimed at eliminating defective mitochondria, and the failure of this mechanism results in a reduced lifespan and impaired locomotor ability, among other phenotypes. Inhibition of parkin or Pink1 through the induction of stable RNAi transgene in the Ddc-Gal4-expressing neurons results in such phenotypes to model PD. To further evaluate the effects of the overexpression of the Bcl-2 homologue Buffy, we analysed lifespan and climbing ability in both parkin-RNAi- and Pink1-RNAi-expressing flies. In addition, the effect of Buffy overexpression upon parkin-induced developmental eye defects was examined through GMR-Gal4-dependent expression. Curiously, Buffy overexpression produced very different effects: the parkin-induced phenotypes were enhanced, whereas the Pink1-enhanced phenotypes were suppressed. Interestingly, the overexpression of Buffy along with the inhibition of parkin in the neuron-rich eye results in the suppression of the developmental eye defects.

Parkinson Disease

Parkinson disease is a neurodegenerative disorder characterized clinically by tremor, rigidity, bradykinesia, and postural instability and pathologically by loss of nigrostriatal neurons and deposition of alpha-synuclein in neuronal cell bodies and neuritis. Non-motor symptoms such as psychiatric disorders, cognitive abnormalities, sleep dysfunction, autonomic dysfunction, and sensory manifestations are also common. This chapter gives a broad overview of this disorder. Sections cover pathophysiology, genetics, clinical manifestations, and disease course. The chapter also briefly discusses how to make the diagnosis, and alternative conditions that should be considered.

Metabolomic biomarkers as strong correlates of Parkinson disease progression

Objective:To determine whether a Parkinson disease (PD)-specific biochemical signature might be found in the total body metabolic milieu or in the CSF compartment, especially since this disorder has systemic manifestations beyond the progressive loss of dopaminergic nigrostriatal neurons.Methods:Our goal was to discover biomarkers of PD progression. Using ultra-high-performance liquid chromatography linked to gas chromatography and tandem mass spectrometry, we measured concentrations of small-molecule (≤1.5 kDa) constituents of plasma and CSF from 49 unmedicated, mildly affected patients with PD (mean age 61.4 years; mean duration of PD 11.4 months). Specimens were collected twice (baseline and final) at intervals up to 24 months. During this time, mean Unified Parkinson’s Disease Rating Scale (UPDRS) parts 2 + 3 scores increased 47% (from 28.8 to 42.2). Measured compounds underwent unbiased univariate and multivariate analyses, including fitting data into multiple linear regression with variable selection using least absolute shrinkage and selection operator (LASSO).Results:Of 575 identified plasma and 383 CSF biochemicals, LASSO led to selection of 15 baseline plasma constituents with high positive correlation (0.87, p = 2.2e−16) to baseline-to-final change in UPDRS parts 2 + 3 scores. Three of the compounds had xanthine structures, and 4 were either medium- or long-chain fatty acids. For the 15 LASSO-selected biomarkers, pathway enrichment software found no overrepresentation among metabolic pathways. CSF concentrations of the dopamine metabolite homovanillate showed little change between baseline and final collections and minimal correlation with worsening UPDRS parts 2 + 3 scores (0.29, p = 0.041).Conclusions:Metabolomic profiling of plasma yielded strong prediction of PD progression and offered biomarkers that may provide new insights into PD pathogenesis.