"Reframing" dopamine signaling at the intersection of glial networks in the aged Parkinsonian brain as innate Nrf2/Wnt driver: Therapeutical implications.

Dopamine (DA) signaling via G protein-coupled receptors is a multifunctional neurotransmitter and neuroendocrine-immune modulator. The DA nigrostriatal pathway, which controls the motor coordination, progressively degenerates in Parkinson's disease (PD), a most common neurodegenerative disorder (ND) characterized by a selective, age-dependent loss of substantia nigra pars compacta (SNpc) neurons, where DA itself is a primary source of oxidative stress and mitochondrial impairment, intersecting astrocyte and microglial inflammatory networks. Importantly, glia acts as a preferential neuroendocrine-immune DA target, in turn, counter-modulating inflammatory processes. With a major focus on DA intersection within the astrocyte-microglial inflammatory network in PD vulnerability, we herein first summarize the characteristics of DA signaling systems, the propensity of DA neurons to oxidative stress, and glial inflammatory triggers dictating the vulnerability to PD. Reciprocally, DA modulation of astrocytes and microglial reactivity, coupled to the synergic impact of gene-environment interactions, then constitute a further level of control regulating midbrain DA neuron (mDAn) survival/death. Not surprisingly, within this circuitry, DA converges to modulate nuclear factor erythroid 2-like 2 (Nrf2), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless (Wnt)/ß-catenin signaling, a key pathway for mDAn neurogenesis, neuroprotection, and immunomodulation, adding to the already complex "signaling puzzle," a novel actor in mDAn-glial regulatory machinery. Here, we propose an autoregulatory feedback system allowing DA to act as an endogenous Nrf2/Wnt innate modulator and trace the importance of DA receptor agonists applied to the clinic as immune modifiers.

Extracellular Vesicles as Novel Diagnostic and Prognostic Biomarkers for Parkinson's Disease.

The elderly population will significantly increase in the next decade and, with it, the proportion of people affected by age-related diseases. Among them, one of the most invalidating is Parkinson's disease (PD), characterized by motor- and non-motor dysfunctions which strongly impair the quality of life of affected individuals. PD is characterized by the progressive degeneration of dopaminergic neurons, with consequent dopamine depletion, and the accumulation of misfolded α-synuclein aggregates. Although 150 years have passed since PD first description, no effective therapies are currently available, but only palliative treatments. Importantly, PD is often diagnosed when the neuronal loss is elevated, making difficult any therapeutic intervention. In this context, two key challenges remain unanswered: (i) the early diagnosis to avoid the insurgence of irreversible symptoms; and (ii) the reliable monitoring of therapy efficacy. Research strives to identify novel biomarkers for PD diagnosis, prognosis, and therapeutic follow-up. One of the most promising sources of biomarkers is represented by extracellular vesicles (EVs), a heterogeneous population of nanoparticles, released by all cells in the microenvironment. Brain-derived EVs are able to cross the blood-brain barrier, protecting their payload from enzymatic degradation, and are easily recovered from biofluids. Interestingly, EV content is strongly influenced by the specific pathophysiological status of the donor cell. In this manuscript, the role of EVs as source of novel PD biomarkers is discussed, providing all recent findings concerning relevant proteins and miRNAs carried by PD patient-derived EVs, from several biological specimens. Moreover, the contribution of mitochondria-derived EVs will be dissected. Finally, the promising possibility to use EVs as source of markers to monitor PD therapy efficacy will be also examined. In the future, larger cohort studies will help to validate these EV-associated candidates, that might be effectively used as non-invasive and robust source of biomarkers for PD.

Extracellular Vesicles as Nanotherapeutics for Parkinson's Disease.

Extracellular vesicles (EVs) are naturally occurring membranous structures secreted by normal and diseased cells, and carrying a wide range of bioactive molecules. In the central nervous system (CNS), EVs are important in both homeostasis and pathology. Through receptor-ligand interactions, direct fusion, or endocytosis, EVs interact with their target cells. Accumulating evidence indicates that EVs play crucial roles in the pathogenesis of many neurodegenerative disorders (NDs), including Parkinson's disease (PD). PD is the second most common ND, characterized by the progressive loss of dopaminergic (DAergic) neurons within the Substantia Nigra pars compacta (SNpc). In PD, EVs are secreted by both neurons and glial cells, with either beneficial or detrimental effects, via a complex program of cell-to-cell communication. The functions of EVs in PD range from their etiopathogenetic relevance to their use as diagnostic tools and innovative carriers of therapeutics. Because they can cross the blood-brain barrier, EVs can be engineered to deliver bioactive molecules (e.g., small interfering RNAs, catalase) within the CNS. This review summarizes the latest findings regarding the role played by EVs in PD etiology, diagnosis, prognosis, and therapy, with a particular focus on their use as novel PD nanotherapeutics.

Glia-Derived Extracellular Vesicles in Parkinson's Disease.

Glial cells are fundamental players in the central nervous system (CNS) development and homeostasis, both in health and disease states. In Parkinson's disease (PD), a dysfunctional glia-neuron crosstalk represents a common final pathway contributing to the chronic and progressive death of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc). Notably, glial cells communicating with each other by an array of molecules, can acquire a "beneficial" or "destructive" phenotype, thereby enhancing neuronal death/vulnerability and/or exerting critical neuroprotective and neuroreparative functions, with mechanisms that are actively investigated. An important way of delivering messenger molecules within this glia-neuron cross-talk consists in the secretion of extracellular vesicles (EVs). EVs are nano-sized membranous particles able to convey a wide range of molecular cargoes in a controlled way, depending on the specific donor cell and the microenvironmental milieu. Given the dual role of glia in PD, glia-derived EVs may deliver molecules carrying various messages for the vulnerable/dysfunctional DAergic neurons. Here, we summarize the state-of-the-art of glial-neuron interactions and glia-derived EVs in PD. Also, EVs have the ability to cross the blood brain barrier (BBB), thus acting both within the CNS and outside, in the periphery. In these regards, this review discloses the emerging applications of EVs, with a special focus on glia-derived EVs as potential carriers of new biomarkers and nanotherapeutics for PD.

Boosting Antioxidant Self-defenses by Grafting Astrocytes Rejuvenates the Aged Microenvironment and Mitigates Nigrostriatal Toxicity in Parkinsonian Brain via an Nrf2-Driven Wnt/ß-Catenin Prosurvival Axis.

Astrocyte (As) bidirectional dialog with neurons plays a fundamental role in major homeostatic brain functions, particularly providing metabolic support and antioxidant self-defense against reactive oxygen (ROS) and nitrogen species (RNS) via the activation of NF-E2-related factor 2 (Nrf2), a master regulator of oxidative stress. Disruption of As-neuron crosstalk is chiefly involved in neuronal degeneration observed in Parkinson's disease (PD), the most common movement disorder characterized by the selective degeneration of dopaminergic (DAergic) cell bodies of the substantia nigra (SN) pars compacta (SNpc). Ventral midbrain (VM)-As are recognized to exert an important role in DAergic neuroprotection via the expression of a variety of factors, including wingless-related MMTV integration site 1 (Wnt1), a principal player in DAergic neurogenesis. However, whether As, by themselves, might fulfill the role of chief players in DAergic neurorestoration of aged PD mice is presently unresolved. Here, we used primary postnatal mouse VM-As as a graft source for unilateral transplantation above the SN of aged 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice after the onset of motor symptoms. Spatio-temporal analyses documented that the engrafted cells promoted: (i) a time-dependent nigrostriatal rescue along with increased high-affinity synaptosomal DA uptake and counteraction of motor deficit, as compared to mock-grafted counterparts; and (ii) a restoration of the impaired microenvironment via upregulation of As antioxidant self-defense through the activation of Nrf2/Wnt/ß-catenin signaling, suggesting that grafting As has the potential to switch the SN neurorescue-unfriendly environment to a beneficial antioxidant/anti-inflammatory prosurvival milieu. These findings highlight As-derived factors/mechanisms as the crucial key for successful therapeutic outcomes in PD.