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  perturbations in mitochondrial quality control (MQC) regulatory system in PD and whether these changes are more likely to occur in astrocytes closely associated with neurons or those more distant from them. Materials and Methods: Post-mortem human brain sections from patients with Parkinson's disease were subjected to imaging mass cytometry for individual astrocyte analysis of key proteins across all five OXPHOS complexes and MQC system.
Results: We show the variability in the astrocytic expression of mitochondrial proteins between individuals. In addition, we found that there is evidence of deficiencies in respiratory chain subunit expression within these important glia and changes, particularly in mitochondrial mass, associated with Parkinson's disease and that are not simply a consequence of advancing age1. Meanwhile, significantly low protein abundance of Parkin, a key mitophagy regulator; HSP60, an intramitochondrial chaperone; and mitofusion2, MFN2 were detected in PD astrocytes compared to controls.
Discussion: Our data has revealed that mitochondrial dysfunction is present within astrocytes in PD, involving deficiency in OXPHOS components and key proteins that maintain normal mitochondrial homeostasis and turnover. Further work will aim to understand whether the disturbance in the astrocytic mitochondrial homeostasis is associated with OXPHOS dysfunction within these astrocyte or adjacent neurons.
Conclusion: Our data show that astrocytes, like neurons, are susceptible to mitochondrial defects and that these could impact their reactivity and ability to support neurons in PD.
Conclusions: These results indicate a cell-autonomous effect of pathogenic A53T expression in astrocytes that may contribute to the altered neuronal and synaptic function observed in α-synucleinopathies.
Background: Autophagy is the main intracellular process that clears misfolded proteins, aggregates, and damaged organelles reported in neurodegeneration. Autophagy is impacted in amyotrophic lateral sclerosis (ALS), a relentlessly progressive, paralyzing, and fatal neurodegenerative disease with no effective treatments. Although autophagy modulation offers promise, it is unclear whether activation or inhibition of autophagy is desirable given the contradictory effects of autophagy manipulations in ALS mouse models. We propose that differential cell-type-specific autophagy regulation may contribute to the disparity. The status of protein homeostasis in neuroglia constituting a large proportion of central nervous system is unknown. We hypothesized that autophagy is impaired in glial cells of the ALS SOD1G93A mice. Using a novel autophagy reporter mouse model, we quantified autophagic rate in SOD1G93A astrocytes, oligodendrocytes, and microglia.
Methods: Autophagy reporter mice were crossbred with SOD1G93A mice. Lumbar spinal cords were collected from offspring mice at pre- symptomatic and symptomatic disease stages. GFAP, Iba1, or Olig2 immunohistochemistry followed by confocal microscopy was used to identify astrocytes, microglia, and oligodendrocytes respectively. The level of autophagy pathway vesicles (autolysosomes and autophagosomes) was quantified. The autophagic rate was assessed using autolysosomes to autophagosomes ratio.
Results and Discussion: The autophagic rate was higher in adult neuroglia compared to young, where a significant increase was observed in oligodendrocytes (n=5,p<0.01). In SOD1G93A mice, both astrocytes and microglia contained increased numbers of autolysosomes, leading to a significantly increased autophagic rate in astrocytes of symptomatic SOD1G93A mice compared to controls (n=5,p<0.001). Autophagic rate in SOD1G93A oligodendrocytes was comparable to controls. Conclusion: We have uncovered glial cell-type-specific differences in autophagic rate, notably upregulated autophagy in astrocytes and microglia in a mouse model of ALS. These findings identify a new role of glial autophagy in ALS abnormal proteostasis. The differential autophagy capacity suggests cell-type-specific targeting approaches are required for optimal autophagy modulation for ALS.
Glial and vascular contributions to neurodegenerative diseases
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Monitoring in vivo autophagy dynamics in neuroglia reveals upregulated astrocytic autophagy in an amyotrophic lateral sclerosis mouse model
Nirma Perera1, Subhavi De Silva1, Fatemeh Zanganeh1,
Doris Tomas1, Bradley Turner1
1Florey Institute of Neuroscience, Melbourne, Australia
   PP42
Dysregulation of astrocytic calcium signaling and gliotransmitter release in mouse models of α-synucleopathies
Carmen Nanclares1, Jonah Poynter1, Hector A. Martell- Martinez1, Alfonso Araque1, Paulo Kofuji1, Michael K. Lee1,2, Ana Covelo1,3,4
1Department of Neuroscience, University of Minnesota. , Minneapolis, USA, 2Institute for Translational Neuroscience, University of Minnesota. , Minneapolis, USA, 3Institut National de la Santé et de la Recherche Médicale (INSERM), U1215 NeuroCentre Magendie , Bordeaux, France, 4University of Bordeaux, Bordeaux, France
 Background: α-synuclein (α-syn) is a major component of Lewy bodies and Lewy neurites appearing in the postmortem brain of Parkinson's disease and other α-synucleinopathies. While most studies of α-synucleinopathies have focused on neuronal and synaptic alterations as well as dysfunctions of the astrocytic homeostatic roles, whether the bidirectional astrocyte-neuronal communication is affected in these diseases remains unknown.
Materials and Methods: We have combined astrocytic calcium (Ca2+) imaging and neuronal electrophysiological recordings in hippocampal slices of several transgenic mouse models related to α-synucleinopathies, i.e., mice expressing high and low levels of the human A53T mutant α-synuclein (G2-3 and H5 mice, respectively) globally or selectively in neurons (iSyn mice), mice expressing human wildtype α-synuclein (I2-2 mice), and mice expressing A30P mutant α-synuclein (O2 mice).
Results: We have found that compared to non-transgenic mice, astrocytes in G2-3 mice at different ages (1-6 months) displayed a Ca2+ hyperexcitability that was independent of neurotransmitter receptor activation, suggesting that the expression of α-synuclein mutant A53T altered the intrinsic properties of astrocytes. Similar dysregulation of the astrocyte Ca2+ signal was present in H5 mice, but not in I2-2 and O2 mice, indicating α-synuclein mutant-specific effects. Moreover, astrocyte Ca2+ hyperexcitability was absent in mice expressing the α-synuclein mutant A53T selectively in neurons, indicating that the effects on astrocytes were cell-autonomous. Consistent with these effects, glutamatergic gliotransmission was enhanced in G2-3 and H5 mice, but was unaffected in I2-2, O2 and iSyn mice.
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