scholarly journals Metabolic response to Parkinson’s disease recapitulated by the haploinsufficient phenotype of diploid yeast cells hemizygous for the adrenodoxin reductase gene

2019 ◽  
Author(s):  
Duygu Dikicioglu ◽  
James W. M. T. Coxon ◽  
Stephen G. Oliver
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cellular Response ◽  
Iron Homeostasis ◽  
Metabolic Response ◽  
Single Copy ◽  
Yeast Cells ◽  
Dopaminergic Neurodegeneration ◽  
Iron Assimilation ◽  
Adrenodoxin Reductase

AbstractAdrenodoxin reductase, a widely conserved mitochondrial P450 protein, catalyses essential steps in steroid hormone biosynthesis and is highly expressed in the adrenal cortex. The yeast adrenodoxin reductase homolog, Arh1p, is involved in cytoplasmic and mitochondrial iron homeostasis and is required for activity of enzymes containing an Fe-S cluster. In this paper, we investigated the response of yeast to the loss of a single copy of ARH1, an oxidoreductase of the mitochondrial inner membrane, which is among the few mitochondrial proteins that is essential for viability in yeast. The phenotypic, transcriptional, proteomic, and metabolic landscape indicated that Saccharomyces cerevisiae successfully adapted to this loss, displaying an apparently dosage-insensitive cellular response. However, a considered investigation of transcriptional regulation in ARH1-impaired yeast highlighted that a significant hierarchical reorganisation occurred, involving the iron assimilation and tyrosine biosynthetic processes. The interconnected roles of the iron and tyrosine pathways, coupled with oxidative processes, are of interest beyond yeast since they are involved in dopaminergic neurodegeneration associated with Parkinson’s disease. The identification of similar responses in yeast suggest that this simple eukaryote could have potential as a model system for investigating the regulatory mechanisms leading to the initiation and progression of early disease responses in humans.

scholarly journals Metabolic response to Parkinson's disease recapitulated by the haploinsufficient diploid yeast cells hemizygous for the adrenodoxin reductase gene

2019 ◽  
Vol 15 (5) ◽  
pp. 340-347
Author(s):  
Duygu Dikicioglu ◽  
James W. M. T. Coxon ◽  
Stephen G. Oliver
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Metabolic Response ◽  
Early Stage ◽  
Disease Model ◽  
Yeast Cells ◽  
Iron Assimilation ◽  
Reductase Gene ◽  
Adrenodoxin Reductase ◽  
Tyrosine Biosynthesis

ARH1-impaired yeast reorganises iron assimilation and tyrosine biosynthesis, suggesting its potential as early-stage Parkinson's disease model, since patient metabolic responses implicate interconnection between these pathways.

scholarly journals TFE3-Mediated Autophagy is Involved in Dopaminergic Neurodegeneration in Parkinson’s Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Xin He ◽  
Yue Xie ◽  
Qiongping Zheng ◽  
Zeyu Zhang ◽  
Shanshan Ma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Transcription Factor ◽  
Dopaminergic Neurons ◽  
Essential Role ◽  
Dopaminergic Neurodegeneration ◽  
Promising Strategy ◽  
Progressive Loss ◽  
Mptp Model

Impairment of autophagy has been strongly implicated in the progressive loss of nigral dopaminergic neurons in Parkinson’s disease (PD). Transcription factor E3 (TFE3), an MiTF/TFE family transcription factor, has been identified as a master regulator of the genes that are associated with lysosomal biogenesis and autophagy. However, whether TFE3 is involved in parkinsonian neurodegeneration remains to be determined. In this study, we found decreased TFE3 expression in the nuclei of the dopaminergic neurons of postmortem human PD brains. Next, we demonstrated that TFE3 knockdown led to autophagy dysfunction and neurodegeneration of dopaminergic neurons in mice, implying that reduction of nuclear TFE3 may contribute to autophagy dysfunction-mediated cell death in PD. Further, we showed that enhancement of autophagy by TFE3 overexpression dramatically reversed autophagy downregulation and dopaminergic neurons loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Taken together, these findings demonstrate that TFE3 plays an essential role in maintaining autophagy and the survival of dopaminergic neurons, suggesting TFE3 activation may serve as a promising strategy for PD therapy.

scholarly journals Multiple genetic pathways regulating lifespan extension are neuroprotective in a G2019S LRRK2 nematode model of Parkinson’s disease

2020 ◽  
Author(s):  
Megan M. Senchuk ◽  
Jeremy M. Van Raamsdonk ◽  
Darren J. Moore
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Late Onset ◽  
Lifespan Extension ◽  
Disease Manifestation ◽  
Genetic Pathways ◽  
Dopaminergic Neurodegeneration ◽  
Age Related ◽  
Increased Risk ◽  
Extended Longevity

AbstractBackgroundMutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of late-onset, familial Parkinson’s disease (PD), and LRRK2 variants are associated with increased risk for sporadic PD. While advanced age represents the strongest risk factor for disease development, it remains unclear how different age-related pathways interact to regulate LRRK2-driven late-onset PD.FindingsIn this study, we employ a C.elegans model expressing PD-linked G2019S LRRK2 to examine the interplay between age-related pathways and LRRK2-induced dopaminergic neurodegeneration. We find that multiple genetic pathways that regulate lifespan extension can provide robust neuroprotection against mutant LRRK2. However, the level of neuroprotection does not strictly correlate with the magnitude of lifespan extension, suggesting that lifespan can be experimentally dissociated from neuroprotection. Using tissue-specific RNAi, we demonstrate that lifespan-regulating pathways, including insulin/IGF-1 signaling, TOR, and mitochondrial respiration, can be directly manipulated in neurons to mediate neuroprotection. We extend this finding for AGE-1/PI3K, where pan-neuronal versus dopaminergic neuronal restoration of AGE-1 reveals both cell-autonomous and non-cell-autonomous neuroprotective mechanisms downstream of insulin signaling.ConclusionsOur data demonstrate the importance of distinct lifespan-regulating pathways in the pathogenesis of LRRK2-linked PD, and suggest that extended longevity is broadly neuroprotective via the actions of these pathways at least in part within neurons. This study further highlights the complex interplay that occurs between cells and tissues during organismal aging and disease manifestation.

scholarly journals TGF-β/Smad3 Signalling Modulates GABA Neurotransmission: Implications in Parkinson’s Disease

2020 ◽  
Vol 21 (2) ◽  
pp. 590 ◽  
Author(s):  
Mª Muñoz ◽  
Nerea de la Fuente ◽  
Amelia Sánchez-Capelo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Side Effects ◽  
Pathological Features ◽  
Therapeutic Approaches ◽  
Brain Nuclei ◽  
Dopaminergic Neurodegeneration ◽  
Cognitive Alterations ◽  
Gaba Neurotransmission

γ-Aminobutiryc acid (GABA) is found extensively in different brain nuclei, including parts involved in Parkinson’s disease (PD), such as the basal ganglia and hippocampus. In PD and in different models of the disorder, an increase in GABA neurotransmission is observed and may promote bradykinesia or L-Dopa-induced side-effects. In addition, proteins involved in GABAA receptor (GABAAR) trafficking, such as GABARAP, Trak1 or PAELR, may participate in the aetiology of the disease. TGF-β/Smad3 signalling has been associated with several pathological features of PD, such as dopaminergic neurodegeneration; reduction of dopaminergic axons and dendrites; and α-synuclein aggregation. Moreover, TGF-β/Smad3 intracellular signalling was recently shown to modulate GABA neurotransmission in the context of parkinsonism and cognitive alterations. This review provides a summary of GABA neurotransmission and TGF-β signalling; their implications in PD; and the regulation of GABA neurotransmission by TGF-β/Smad3. There appear to be new possibilities to develop therapeutic approaches for the treatment of PD using GABA modulators.

scholarly journals miR-425 deficiency promotes necroptosis and dopaminergic neurodegeneration in Parkinson’s disease

2019 ◽  
Vol 10 (8) ◽  
Author(s):  
Yong-Bo Hu ◽  
Yong-Fang Zhang ◽  
Hao Wang ◽  
Ru-Jing Ren ◽  
Hai-Lun Cui ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurodegeneration

scholarly journals Found in Translation: The Utility of C. elegans Alpha-Synuclein Models of Parkinson’s Disease

2019 ◽  
Vol 9 (4) ◽  
pp. 73 ◽  
Author(s):  
Anthony Gaeta ◽  
Kim Caldwell ◽  
Guy Caldwell
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alpha Synuclein ◽  
Dopamine Neurons ◽  
Genetic Modifiers ◽  
Transgenic Expression ◽  
C Elegans ◽  
Dopaminergic Neurodegeneration ◽  
Cellular Phenotypes ◽  
Functional Mechanisms

Parkinson’s Disease (PD) is the second-most common neurodegenerative disease in the world, yet the fundamental and underlying causes of the disease are largely unknown, and treatments remain sparse and impotent. Several biological systems have been employed to model the disease but the nematode roundworm Caenorhabditis elegans (C. elegans) shows unique promise among these to disinter the elusive factors that may prevent, halt, and/or reverse PD phenotypes. Some of the most salient of these C. elegans models of PD are those that position the misfolding-prone protein alpha-synuclein (α-syn), a hallmark pathological component of PD, as the primary target for scientific interrogation. By transgenic expression of human α-syn in different tissues, including dopamine neurons and muscle cells, the primary cellular phenotypes of PD in humans have been recapitulated in these C. elegans models and have already uncovered multifarious genetic factors and chemical compounds that attenuate dopaminergic neurodegeneration. This review describes the paramount discoveries obtained through the application of different α-syn models of PD in C. elegans and highlights their established utility and respective promise to successfully uncover new conserved genetic modifiers, functional mechanisms, therapeutic targets and molecular leads for PD with the potential to translate to humans.

Sign in / Sign up

Export Citation Format

Share Document