scholarly journals Ageing and MPTP-sensitivity depend on molecular and ultrastructural signatures of Astroglia and Microglia in mice nigra

2020 ◽  
Author(s):  
PL Abhilash ◽  
Upasna Bharti ◽  
Haorei Yarreiphang ◽  
Mariamma Philip ◽  
Rashmi Santhosh Kumar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Old Age ◽  
Middle Age ◽  
Strain Differences ◽  
Experimental Models ◽  
Data Availability ◽  
Specific Distribution ◽  
Tnf Α ◽  
Objective Evidence

ABSTRACTGlia show region-specific distribution in CNS and often mal-adapt to age-associated alterations in their niche. Some studies on autopsied nigra of Parkinson’s disease (PD) patients and experimental models propose gliosis as a putative trigger of neuronal loss. Epidemiological studies propose an ethnic bias in PD prevalence, as Caucasians are more susceptible than non-whites. Similarly, different mice strains are variably sensitive to MPTP. We had earlier likened divergent MPTP-sensitivity of C57BL/6J and CD-1 mice with differential susceptibility to PD based on differences in neuronal numbers.Here we examined whether the variability was also incumbent to inter-strain differences in glial features. Stereological counts showed more microglia and fewer astrocytes in the nigra of MPTP-susceptible normal C57BL/6J mice, suggesting persistence of an immune-vigilant state. Pronounced MPTP-induced microgliosis and astrogliosis in both strains suggest glial involvement in pathogenesis. ELISA-based estimation of pro-inflammatory cytokines in the ventral midbrain revealed middle-age specific augmentation of TNF-α and IL-6 that reduced at old-age, suggesting middle-age as a critical, inflamm-aging associated time-point. IL-1β levels declined gradually. Inter-strain differences in TNF-α, including that seen post-MPTP, persisted across ageing while IL-6 and IL-1β showed upregulation at old-age. Levels of anti-inflammatory cytokine TGF-β were higher in CD-1. The enzymes MAO-A, MAO-B and iNOS were upregulated in both strains upon MPTP-challenge. Enhancement in fracktalkine and hemeoxygenase-1, post-MPTP, may be neuronal compensatory signals. Most importantly, ultrastructural observations of elongated glial mitochondria vis-à-vis the shrunken ones in neurons, suggest upscaling of glial functions with neurotoxic consequences. Thus, glia could be key modulators of ageing and disease-susceptibility.Significance statementPeople of Caucasians ancestry are more susceptible to Parkinson’s disease, than the Asians, for reasons not completely understood. Surprisingly, their admixed population “the Anglo-Indians” that lives in India; are much less prone. We designed a disease model around two different laboratory mice i.e. C57BL/6 and CD-1 mice and extrapolated the results to the ethnicities, using a neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). Our study provides objective evidence that astroglia are inherently more and microglia fewer in the mice that resist MPTP. They secret low levels of neuroinflammatory proteins and their gut microbiota is typical. The glial mitochondria may hold the key to cure neurodegeneration.Data availability statementThe data that support the findings of this study are available from the corresponding author upon request.

scholarly journals Aging and MPTP-Sensitivity Depend on Molecular and Ultrastructural Signatures of Astroglia and Microglia in Mice Substantia Nigra

2021 ◽  
Author(s):  
PL Abhilash ◽  
Upasna Bharti ◽  
Mariamma Philip ◽  
Santhosh Kumar Rashmi ◽  
Trichur R Raju ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Old Age ◽  
Inflammatory Cytokines ◽  
Middle Age ◽  
Critical Role ◽  
Experimental Models ◽  
Substantia Nigra Pars Compacta ◽  
Specific Distribution ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract BackgroundBoth astroglia and microglia show region-specific distribution pattern in the central nervous system and often maladapt to age-associated alterations within their niche. Studies on autopsied substantia nigra of Parkinson’s disease (PD) patients and experimental models propose gliosis as a trigger for neuronal loss. Epidemiological studies propose an ethnic bias in PD prevalence, since Caucasians are more susceptible than non-whites living in Asia and Africa. Similarly, different mice strains are variably sensitive to the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). We had earlier likened divergent MPTP-sensitivity of C57BL/6J and CD-1 mice with differential susceptibility to PD, based on differences in neuronal numbers.MethodsHere we examined whether the variable susceptibility was also incumbent to inter-strain differences in the glial features in the substantia nigra pars compacta (SNpc) of C57BL/6J and CD-1 mice. We performed unbiased stereology to quantify iba-1 immunoreactive microglia and s100β immunopositive astroglia on immunohistochemically stained sections. Further, ELISA based estimation of pro- inflammatory and anti-inflammatory cytokines was supplemented with estimation of enzymes like fractalkine, hemeoxygenase, and monoamine oxidases A and B. Electron microscopy was performed to compare the effects on the organelles.ResultsStereological counts showed more microglia and fewer astrocytes in the substantia nigra of MPTP-susceptible normal C57BL/6J mice, which suggests persistence of an immune-vigilant state. MPTP caused induction of microgliosis and astrogliosis in both strains, suggesting the involvement of these cells in pathogenesis. ELISA of pro-inflammatory cytokines in the ventral-midbrain revealed augmentation of TNF-α and IL-6 at middle-age in both strains that reduced at old-age, suggesting middle-age as a critical, inflamm-aging associated time-point. TNF-α levels were persistently high in C57BL/6J, through aging and post-MPTP; while IL-6 and IL-1β were upregulated at old-age. CD-1 had higher levels of anti-inflammatory cytokine TGF-β. MPTP-challenge caused upregulation of enzymes MAO-A, MAO-B and iNOS in both strains. Post-MPTP enhancement in fractalkine and hemeoxygenase-1, may be neuronal compensatory signals. Lastly, ultrastructural observations of elongated mitochondria in astroglia and microglia vis-à-vis the shrunken ones in neurons, suggest upscaling of their functions with neurotoxic consequences.ConclusionsThus, astroglia and microglia play a critical role in modulating aging and the susceptibility of an individual to PD.

scholarly journals The Prion-Like Spreading of Alpha-Synuclein in Parkinson’s Disease: Update on Models and Hypotheses

2021 ◽  
Vol 22 (15) ◽  
pp. 8338
Author(s):  
Asad Jan ◽  
Nádia Pereira Gonçalves ◽  
Christian Bjerggaard Vaegter ◽  
Poul Henning Jensen ◽  
Nelson Ferreira
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Alpha Synuclein ◽  
Experimental Models ◽  
Cellular Factors ◽  
Recent Developments ◽  
Novel Targets ◽  
Presynaptic Protein

The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson’s disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of endogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic propagation of α-syn pathology in the context of neuronal vulnerability and highlight the potential utility of novel experimental models of synucleinopathies.

scholarly journals Correlates of the discrepancy between objective and subjective cognitive functioning in non-demented patients with Parkinson’s disease

2021 ◽  
Author(s):  
Mattia Siciliano ◽  
Lugi Trojano ◽  
Rosa De Micco ◽  
Valeria Sant’Elia ◽  
Alfonso Giordano ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Linear Regression ◽  
Cognitive Functioning ◽  
Rating Scale ◽  
Regression Analyses ◽  
Chi Square ◽  
Cognitive Measure ◽  
Objective Evidence ◽  
Cognitive Discrepancy

Abstract Background Subjective complaints of cognitive deficits are not necessarily consistent with objective evidence of cognitive impairment in Parkinson’s disease (PD). Here we examined the factors associated with the objective-subjective cognitive discrepancy. Methods We consecutively enrolled 90 non-demented patients with PD who completed the Parkinson’s Disease Cognitive Functional Rating Scale (subjective cognitive measure) and the Montreal Cognitive Assessment (MoCA; objective cognitive measure). The patients were classified as “Overestimators”, “Accurate estimators”, and “Underestimators” on the basis of the discrepancy between the objective vs. subjective cognitive measures. To identify the factors distinguishing these groups from each other, we used chi-square tests or one-way analyses of variance, completed by logistic and linear regression analyses. Results Forty-nine patients (54.45%) were classified as “Accurate estimators”, 29 (32.22%) as “Underestimators”, and 12 (13.33%) as “Overestimators”. Relative to the other groups, the “Underestimators” scored higher on the Fatigue Severity Scale (FSS), Beck Depression Inventory (BDI), and Parkinson Anxiety Scale (p < 0.01). Logistic regression confirmed that FSS and BDI scores distinguished the “Underestimators” group from the others (p < 0.05). Linear regression analyses also indicated that FSS and BDI scores positively related to objective-subjective cognitive discrepancy (p < 0.01). “Overestimators” scored lower than other groups on the MoCA’s total score and attention and working memory subscores (p < 0.01). Conclusion In more than 45% of consecutive non-demented patients with PD, we found a ‘mismatch’ between objective and subjective measures of cognitive functioning. Such discrepancy, which was related to the presence of fatigue and depressive symptoms and frontal executive impairments, should be carefully evaluated in clinical setting.

scholarly journals Corticostriatal Plastic Changes in Experimental L-DOPA-Induced Dyskinesia

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Veronica Ghiglieri ◽  
Vincenza Bagetta ◽  
Valentina Pendolino ◽  
Barbara Picconi ◽  
Paolo Calabresi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Experimental Models ◽  
Striatal Neurons ◽  
Da Receptors ◽  
Electrophysiological Studies ◽  
Plastic Changes ◽  
Stimulation Of

In Parkinson’s disease (PD), alteration of dopamine- (DA-) dependent striatal functions and pulsatile stimulation of DA receptors caused by the discontinuous administration of levodopa (L-DOPA) lead to a complex cascade of events affecting the postsynaptic striatal neurons that might account for the appearance of L-DOPA-induced dyskinesia (LID). Experimental models of LID have been widely used and extensively characterized in rodents and electrophysiological studies provided remarkable insights into the inner mechanisms underlying L-DOPA-induced corticostriatal plastic changes. Here we provide an overview of recent findings that represent a further step into the comprehension of mechanisms underlying maladaptive changes of basal ganglia functions in response to L-DOPA and associated to development of LID.

scholarly journals The activities of LRRK2 and GCase are positively correlated in clinical biospecimens and experimental models of Parkinson’s disease

2021 ◽  
Author(s):  
Maria Kedariti ◽  
Emanuele Frattini ◽  
Pascale Baden ◽  
Susanna Cogo ◽  
Laura Civiero ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Experimental Models ◽  
Cellular Functions ◽  
Gene Encoding ◽  
Cellular Models ◽  
Lrrk2 Kinase ◽  
The Impact ◽  
Lrrk2 Kinase Activity

AbstractLRRK2 is a kinase involved in different cellular functions, including autophagy, endolysosomal pathways and vesicle trafficking. Mutations in LRRK2 cause autosomal dominant forms of Parkinson’s disease (PD). Heterozygous mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), are the most common genetic risk factors for PD. Moreover, GCase function is altered in idiopathic PD and in other genetic forms of the disease. Recent work suggests that LRRK2 kinase activity can regulate GCase function. However, both a positive and a negative correlation have been described. To gain insights into the impact of LRRK2 on GCase, we investigated GCase levels and activity in LRRK2 G2019S knockin mice, in clinical biospecimens from PD patients carrying this mutation and in patient-derived cellular models. In these models we found a positive correlation between the activities of LRRK2 and GCase, which was further confirmed in cell lines with genetic and pharmacological manipulation of LRRK2 kinase activity. Overall, our study indicates that LRRK2 kinase activity affects both the levels and the catalytic activity of GCase.

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