scholarly journals Astrocytic Changes in Mitochondrial Oxidative Phosphorylation Protein Levels in Parkinson's Disease

2021 ◽  
Author(s):  
Chun Chen ◽  
Emily Mossman ◽  
Philippa Malko ◽  
David McDonald ◽  
Alasdair P. Blain ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Protein Levels

Mitochondrial oxidative phosphorylation defects in parkinson's disease

1991 ◽  
Vol 30 (3) ◽  
pp. 332-339 ◽  
Author(s):  
John M. Shoffner ◽  
Ray L. Watts ◽  
Jorge L. Juncos ◽  
Antonio Torroni ◽  
Douglas C. Wallace
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Oxidative Phosphorylation

Mitochondrial oxidative phosphorylation defects in Parkinson's disease

1992 ◽  
Vol 32 (1) ◽  
pp. 113-114 ◽  
Author(s):  
D. C. Wallace ◽  
J. M. Shoffner ◽  
R. L. Watts ◽  
J. L. Juncos ◽  
Antonio Torroni
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Oxidative Phosphorylation

scholarly journals Imaging mass cytometry reveals generalised deficiency in OXPHOS complexes in Parkinson’s disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Chun Chen ◽  
David McDonald ◽  
Alasdair Blain ◽  
Ashwin Sachdeva ◽  
Laura Bone ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Dopaminergic Neurons ◽  
Neuronal Response ◽  
Proteomic Profiling ◽  
Mass Cytometry ◽  
And Control

AbstractHere we report the application of a mass spectrometry-based technology, imaging mass cytometry, to perform in-depth proteomic profiling of mitochondrial complexes in single neurons, using metal-conjugated antibodies to label post-mortem human midbrain sections. Mitochondrial dysfunction, particularly deficiency in complex I has previously been associated with the degeneration of dopaminergic neurons in Parkinson’s disease. To further our understanding of the nature of this dysfunction, and to identify Parkinson’s disease specific changes, we validated a panel of antibodies targeting subunits of all five mitochondrial oxidative phosphorylation complexes in dopaminergic neurons from Parkinson’s disease, mitochondrial disease, and control cases. Detailed analysis of the expression profile of these proteins, highlighted heterogeneity between individuals. There is a widespread decrease in expression of all complexes in Parkinson’s neurons, although more severe in mitochondrial disease neurons, however, the combination of affected complexes varies between the two groups. We also provide evidence of a potential neuronal response to mitochondrial dysfunction through a compensatory increase in mitochondrial mass. This study highlights the use of imaging mass cytometry in the assessment and analysis of expression of oxidative phosphorylation proteins, revealing the complexity of deficiencies of these proteins within individual neurons which may contribute to and drive neurodegeneration in Parkinson’s disease.

scholarly journals Fibroblasts from idiopathic Parkinson’s disease exhibit deficiency of lysosomal glucocerebrosidase activity associated with reduced levels of the trafficking receptor LIMP2

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ria Thomas ◽  
Elizabeth B. Moloney ◽  
Zachary K. Macbain ◽  
Penelope J. Hallett ◽  
Ole Isacson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Enzyme Activity ◽  
Current Data ◽  
Lysosomal Hydrolase ◽  
Protein Levels ◽  
Control Subjects ◽  
Er Retention ◽  
Trafficking Receptor ◽  
N370s Mutation

AbstractLysosomal dysfunction is a central pathway associated with Parkinson’s disease (PD) pathogenesis. Haploinsufficiency of the lysosomal hydrolase GBA (encoding glucocerebrosidase (GCase)) is one of the largest genetic risk factors for developing PD. Deficiencies in the activity of the GCase enzyme have been observed in human tissues from both genetic (harboring mutations in the GBA gene) and idiopathic forms of the disease. To understand the mechanisms behind the deficits of lysosomal GCase enzyme activity in idiopathic PD, this study utilized a large cohort of fibroblast cells from control subjects and PD patients with and without mutations in the GBA gene (N370S mutation) (control, n = 15; idiopathic PD, n = 31; PD with GBA N370S mutation, n = 6). The current data demonstrates that idiopathic PD fibroblasts devoid of any mutations in the GBA gene also exhibit reduction in lysosomal GCase activity, similar to those with the GBA N370S mutation. This reduced GCase enzyme activity in idiopathic PD cells was accompanied by decreased expression of the GBA trafficking receptor, LIMP2, and increased ER retention of the GBA protein in these cells. Importantly, in idiopathic PD fibroblasts LIMP2 protein levels correlated significantly with GCase activity, which was not the case in control subjects or in genetic PD GBA N370S cells. In conclusion, idiopathic PD fibroblasts have decreased GCase activity primarily driven by altered LIMP2-mediated transport of GBA to lysosome and the reduced GCase activity exhibited by  the genetic GBA N370S derived PD fibroblasts occurs through a different mechanism.

scholarly journals Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110097
Author(s):  
Kui Cui ◽  
Fan Yang ◽  
Turan Tufan ◽  
Muhammad U. Raza ◽  
Yanqiang Zhan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcription Factors ◽  
Disease Model ◽  
Neuronal Loss ◽  
Mrna Levels ◽  
Gene Therapies ◽  
Protein Levels ◽  
Dopaminergic Systems ◽  
And Function

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.

scholarly journals TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease

2017 ◽  
Vol 114 (40) ◽  
pp. 10773-10778 ◽  
Author(s):  
Seong Su Kang ◽  
Zhentao Zhang ◽  
Xia Liu ◽  
Fredric P. Manfredsson ◽  
Matthew J. Benskey ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Death ◽  
Kinase Domain ◽  
Alpha Synuclein ◽  
Mao B ◽  
Protein Levels ◽  
Trkb Receptors ◽  
Alpha Synuclein Aggregation ◽  
Neurotrophic Signaling

BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson’s disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase. Interestingly, α-Syn represses TrkB lipid raft distribution, decreases its internalization, and reduces its axonal trafficking. Moreover, α-Syn also reduces TrkB protein levels via up-regulation of TrkB ubiquitination. Remarkably, dopamine’s metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL) stimulates the interaction between α-Syn and TrkB. Accordingly, MAO-B inhibitor rasagiline disrupts α-Syn/TrkB complex and rescues TrkB neurotrophic signaling, preventing α-Syn–induced dopaminergic neuronal death and restoring motor functions. Hence, our findings demonstrate a noble pathological role of α-Syn in antagonizing neurotrophic signaling, providing a molecular mechanism that accounts for its neurotoxicity in PD.

Increased Striatal mRNA and Protein Levels of the Immunophilin FKBP-12 in Experimental Parkinson's Disease and Identification of FKBP-12-Binding Proteins

2007 ◽  
Vol 6 (10) ◽  
pp. 3952-3961 ◽  
Author(s):  
Anna Nilsson ◽  
Karl Sköld ◽  
Benita Sjögren ◽  
Marcus Svensson ◽  
Johan Pierson ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binding Proteins ◽  
Protein Levels

scholarly journals A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

2021 ◽  
Vol 22 (7) ◽  
pp. 3708
Author(s):  
Jun Ogata ◽  
Kentaro Hirao ◽  
Kenya Nishioka ◽  
Arisa Hayashida ◽  
Yuanzhe Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Peripheral Blood ◽  
Kinase Activity ◽  
Late Onset ◽  
Causative Gene ◽  
Protein Levels ◽  
Wd40 Domain ◽  
Lrrk2 Protein ◽  
Familial Parkinson’S Disease

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.

scholarly journals Dopamine Release Neuroenergetics in Mouse Striatal Slices

2020 ◽  
Author(s):  
Msema Msackyi ◽  
Yuanxin Chen ◽  
Wangchen Tsering ◽  
Ninghan Wang ◽  
Jingyu Zhao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nucleus Accumbens ◽  
Oxidative Phosphorylation ◽  
Neurodegenerative Disorder ◽  
Dorsal Striatum ◽  
Striatal Slices ◽  
Axonal Projections ◽  
Specific Vulnerability ◽  
Da Release

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease. Dopamine (DA) neurons in the substantia nigra par compacta with axonal projections to the dorsal striatum (dSTR) degenerate in PD while in contrast, DA neurons in the ventral tegmental area with axonal projections to the ventral striatum including the nucleus accumbens (NAcc) shell, are largely spared. To understand the pathogenesis of PD, it is important to study the neuroenergetics of DA neurons. This study aims to uncover the relative contribution of glycolysis and oxidative phosphorylation (OxPhos) to evoked DA release in the striatum. We measured evoked DA release in mouse striatal brain slices by fast-scan cyclic voltammetry every 2 minutes. Blocking OxPhos caused a greater reduction in evoked DA release in the dSTR compared to the NAcc shell, and blocking glycolysis caused a greater reduction in evoked DA release in the NAcc shell than in the dSTR. Furthermore, when glycolysis was bypassed in favor of direct OxPhos, evoked DA release in the NAcc shell was decreased by ∼50% over 40 minutes whereas evoked DA release in the dSTR was largely unaffected. These results demonstrated that the dSTR relies primarily on OxPhos for energy production to maintain evoked DA release whereas the NAcc shell relies more on glycolysis. Using two-photon imaging, we consistently found that the oxidation level of the DA terminals was higher in the dSTR than in the NAcc shell. Together, these findings partially explain the specific vulnerability of DA terminals in the dSTR to degeneration in PD.Significant statementThe neuroenergetics of dopaminergic neuron is important to understand Parkinson’s disease (PD), a neurodegenerative disorder associated with mitochondrial dysfunctions. However, the relative contributions of glycolysis and oxidative phosphorylation (OxPhos) to presynaptic energy demands in DA terminals are unclear. We addressed this question by measuring DA release in the dorsal striatum and nucleus accumbens (NAcc) shell of mouse brain using FSCV under reagents blocking different energy systems. We found that the NAcc shell relies on both glycolysis and OxPhos to maintain DA release while the dSTR relies heavily on OxPhos. We demonstrate the different neuroenergetics of DA terminals in these two brain areas, providing new fundamentally important insight into the specific vulnerability of DA terminals in the dSTR to degeneration in PD.

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