Emerging evidence points to reactive glia as a pivotal factor in Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of basal ganglia injury, but whether astrocytes and microglia activation may exacerbate dopaminergic (DAergic) neuron demise and/or contribute to DAergic repair is presently the subject of much debate. Here, we have correlated the loss and recovery of the nigrostriatal DAergic functionality upon acute MPTP exposure with extensive gene expression analysis at the level of the ventral midbrain (VM) and striata (Str) and found a major upregulation of pro-inflammatory chemokines and winglesstype MMTV integration site1 (Wnt1)
BackgroundDopamine-synthesizing (dopaminergic, DA) neurons in the ventral midbrain (VM) constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt)/β-catenin pathway in their progenitors. In Parkinson's disease, DA cell bodies within the substantia nigra pars compacta (SNpc) progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd) receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons.ResultsIn vitro experiments identifie Fzd-1 receptor expression at a mRNA and protein levels in dopamine transporter (DAT) expressing neurons, and demonstrate the ability of exogenous Wnt1 to exert robust neuroprotective effects against Caspase-3 activation, the loss of tyrosine hydroxylase-positive (TH+) neurons and [3H] dopamine uptake induced by different DA-specific insults, including serum and growth factor deprivation, 6-hydroxydopamine and MPTP/MPP+. Co-culture of DA neurons with midbrain astrocytes phenocopies Wnt1 neuroprotective effects, whereas RNA interference-mediated knockdown of Wnt1 in midbrain astrocytes markedly reduces astrocyte-induced TH+ neuroprotection. Likewise, silencing β-catenin mRNA or knocking down Fzd-1 receptor expression in mesencephalic neurons counteract astrocyte-induced TH+ neuroprotection. In vivo experiments document Fzd-1 co-localization with TH+ neurons within the intact SNpc and blockade of Fzd/β-catenin signaling by unilateral infusion of a Fzd/β-catenin antagonist within the SN induces reactive astrocytosis and acutely inhibits TH+ neuron survival in ipsilateral SNpc, an effect efficiently prevented by pharmacological activation of β-catenin signaling within the SNpc.ConclusionThese results defining a novel Wnt1/Fzd-1/β-catenin astrocyte-DA autoprotective loop provide a new mechanistic inside into the regulation of pro-survival processes, with potentially relevant consequences for drug design or drug action in Parkinson's disease.
Aging and exposure to environmental toxins including MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) are strong risk factors for developing Parkinson's disease (PD), a common neurologic disorder characterized by selective degeneration of midbrain dopaminergic (DAergic) neurons and astrogliosis. Aging and PD impair the subventricular zone (SVZ), one of the most important brain regions for adult neurogenesis. Because inflammation and oxidative stress are the hallmarks of aging and PD, we investigated the nature, timing, and signaling mechanisms contributing to aging-induced SVZ stem/neuroprogenitor cell (NPC) inhibition in aging male mice and attempted to determine to what extent manipulation of these pathways produces a functional response in the outcome of MPTP-induced DAergic toxicity. We herein reveal an imbalance of Nrf2-driven antioxidant/anti-inflammatory genes, such as Heme oxygenase1 in the SVZ niche, starting by middle age, amplified upon neurotoxin treatment and associated with an exacerbated proinflammatory SVZ microenvironment converging to dysregulate the Wingless-type MMTV integration site (Wnt)/-catenin signaling, a key regulatory pathway for adult NPCs. In vitro experiments using coculture paradigms uncovered aged microglial proinflammatory mediators as critical inhibitors of NPC proliferative potential. We also found that interruption of PI3K (phosphatidylinositol3-kinase)/Akt and the Wnt/Fzd/-catenin signaling cascades, which switch glycogen synthase kinase 3 (GSK-3) activation on and off, were causally related to the impairment of SVZ-NPCs. Moreover, a synergy between dysfunctional microglia of aging mice and MPTP exposure further inhibited astrocyte proneurogenic properties, including the expression of key Wnts components. Last, pharmacological activation/antagonism studies in vivo and in vitro suggest the potential that aged SVZ manipulation is associated with DAergic functional recovery.
The rapid recovery of smell and taste functions in COVID-19
patients could be attributed to a decrease in interleukin-6
levels rather than central nervous system ischemic injury or
viral damage to neuronal cells. To correlate interleukin-6
levels in COVID-19 patients with olfactory or gustatory
dysfunctions and to investigate the role of IL-6 in the onset of
these disorders, this observational study investigated 67
COVID-19 patients with taste or smell disorders or both, who did
not require intensive care admission, admitted at COVID Hospital
of Policlinico of Bari from March to May 2020. Interleukin-6 was
assayed in COVID-19 patients with taste or smell disturbances at
the time of admission and at the time of swab negativization. At
the same time, patients have been given a specific survey to
evaluate the severity of taste and smell disturbances. Of 125
patients with smell or taste dysfunctions at onset of disease,
67 fulfilled the inclusion criteria, while 58 were excluded
because 35 of them required intensive care admission, 5 were
unable to answer, 5 died, 7 had finished chemotherapy recently,
and 5 refused to participate. The evaluation of taste and smell
disorders was carried out using a survey performed at the time
of admission and at the time of swab negativization. Sinonasal
outcome test 22 (SNOT-22) was used as a reference for olfactory
function assessment, and Taste and Smell Questionnaire Section
of the US NHANES 2011–2014 protocol (CDC 2013b) was used
as reference for gustatory function assessment. A venous blood
sample was taken for each patient to measure IL-6 levels upon
entry and at swab negativization. Interleukin-6 levels in
COVID-19 patients in relation to olfactory or gustatory
disorders were correlated from the time of their admission to
the time of swab negativization. Statistically significant
correlations were obtained between the decrease of interleukin-6
levels and the improvement of smell (
p
value
< 0.05) and taste (
p
= 0.047) functions at
swab negativization. The acquired results demonstrate the key
role of interleukin-6 in the pathogenesis of chemosensitive
disorders in COVID-19 patients.
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