Selective degeneration of dopamine neurons in Parkinson’s disease: emerging roles of altered calcium homeostasis and nucleolar function

e-Neuroforum ◽  
2018 ◽  
Vol 24 (1) ◽  
pp. A1-A9 ◽  
Author(s):  
Rosanna Parlato ◽  
Birgit Liss
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopamine Neurons ◽  
Metabolic Dysfunction ◽  
Vulnerability Factors ◽  
Trigger Factors ◽  
Altered Gene Expression ◽  
Specific Vulnerability ◽  
Altered Gene ◽  
Nucleolar Function

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease. Its classic major motor-symptoms are caused by the progressive loss of dopamine in the striatum, and of dopamine (DA) releasing neurons in the midbrain, particularly within the Substantia nigra (SN). The cause for PD is still unclear, hampering the development of curative therapies. However multiple genetic and environmental PD trigger factors have been identified, pointing to a common, mutually interdependent pathomechanism of cell-specific metabolic dysfunction and altered gene expression. Here, we summarize and discuss these emerging PD-pathomechanisms, that could provide novel potential therapeutic targets, with a focus on altered Ca2+ homeostasis and nucleolar function. We discuss how animal models with impaired nucleolar ribosomal RNA synthesis can enable identification of novel cell-specific vulnerability factors, and how complex homeostatic adaptation of SN DA neurons could enable a flexible adjustment of their functional activity to metabolic needs, but also might render them particularly vulnerable to degenerative triggers and cell-death in PD.

scholarly journals α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Abeer Dagra ◽  
Douglas R. Miller ◽  
Min Lin ◽  
Adithya Gopinath ◽  
Fatemeh Shaerzadeh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Activity ◽  
Dopaminergic Neurons ◽  
Prolonged Exposure ◽  
D2 Receptor ◽  
Neuronal Firing ◽  
Dopamine Neurons ◽  
Loss Of Function ◽  
Therapeutic Implications

AbstractPathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.

scholarly journals The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 598
Author(s):  
Jeswinder Sian-Hulsmann ◽  
Peter Riederer
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Viral Infections ◽  
Genetic Defect ◽  
Lewy Bodies ◽  
Common Denominator ◽  
Metabolic Disturbances ◽  
Trigger Factors ◽  
Protein Clearance ◽  
Sporadic Parkinson’S Disease

The risk of Parkinson’s disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson’s disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder.

scholarly journals Endoplasmic Reticulum Stress Regulators: New Drug Targets for Parkinson’s Disease

2021 ◽  
pp. 1-10
Author(s):  
Vera Kovaleva ◽  
Mart Saarma
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Er Stress ◽  
Protein Misfolding ◽  
Drug Targets ◽  
Dopamine Neurons ◽  
Drug Candidates ◽  
The Unfolded Protein Response

Parkinson’s disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborisation and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2 + dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2 +-homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signalling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1α) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical PD animal models. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.

Transplantation of Embryonic Dopamine Neurons for Severe Parkinson's Disease

2001 ◽  
Vol 344 (10) ◽  
pp. 710-719 ◽  
Author(s):  
Curt R. Freed ◽  
Paul E. Greene ◽  
Robert E. Breeze ◽  
Wei-Yann Tsai ◽  
William DuMouchel ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopamine Neurons

Simvastatin Prevents Neurodegeneration in the MPTP Mouse Model of Parkinson’s Disease via Inhibition of A1 Reactive Astrocytes

2021 ◽  
pp. 1-8
Author(s):  
Ren-Wei Du ◽  
Wen-Guang Bu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Underlying Mechanism ◽  
Reactive Astrocytes ◽  
Dopamine Neurons ◽  
Neuron Death ◽  
Neurologic Disorders

Emerging evidence indicates that A1 reactive astrocytes play crucial roles in the pathogenesis of Parkinson’s disease (PD). Thus, development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat PD. Simvastatin has been touted as a potential neuroprotective agent for neurologic disorders such as PD, but the specific underlying mechanism remains unclear. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and primary astrocytes/neurons were prepared to investigate the effects of simvastatin on PD and its underlying mechanisms in vitro and in vivo. We show that simvastatin protects against the loss of dopamine neurons and behavioral deficits in the MPTP mouse model of PD. We also found that simvastatin suppressed the expression of A1 astrocytic specific markers in vivo and in vitro. In addition, simvastatin alleviated neuron death induced by A1 astrocytes. Our findings reveal that simvastatin is neuroprotective via the prevention of conversion of astrocytes to an A1 neurotoxic phenotype. In light of simvastatin favorable properties, it should be evaluated in the treatment of PD and related neurologic disorders characterized by A1 reactive astrocytes.

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