scholarly journals Changes in Drp1 Function and Mitochondrial Morphology Are Associated with the α-Synuclein Pathology in a Transgenic Mouse Model of Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 885
Author(s):  
Philipp Portz ◽  
Michael K. Lee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Transgene Expression ◽  
Mitochondrial Dynamics ◽  
Transgenic Mouse Model ◽  
Mitochondrial Morphology ◽  
Pathological Changes ◽  
The Relationship

Alterations in mitochondrial function and morphology are associated with many human diseases, including cancer and neurodegenerative diseases. Mitochondrial impairment is linked to Parkinson’s disease (PD) pathogenesis, and alterations in mitochondrial dynamics are seen in PD models. In particular, α-synuclein (αS) abnormalities are often associated with pathological changes to mitochondria. However, the relationship between αS pathology and mitochondrial dynamics remains poorly defined. Herein, we examined a mouse model of α-synucleinopathy for αS pathology-linked alterations in mitochondrial dynamics in vivo. We show that α-synucleinopathy in a transgenic (Tg) mouse model expressing familial PD-linked mutant A53T human αS (TgA53T) is associated with a decrease in Drp1 localization and activity in the mitochondria. In addition, we show that the loss of Drp1 function in the mitochondria is associated with two distinct phenotypes of enlarged neuronal mitochondria. Mitochondrial enlargement was only present in diseased animals and, apart from Drp1, other proteins involved in mitochondrial dynamics are unlikely to cause these changes, as their levels remained mostly unchanged. Further, the levels of Mfn1, a protein that facilitates mitochondrial fusion, was decreased nonspecifically with transgene expression. These results support the view that altered mitochondrial dynamics are a significant neuropathological factor in α-synucleinopathies.

scholarly journals Dl-3-n-Butylphthalide Alleviates Behavioral and Cognitive Symptoms Via Modulating Mitochondrial Dynamics in the A53T-α-Synuclein Mouse Model of Parkinson’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Huiying Li ◽  
Hongquan Wang ◽  
Ling Zhang ◽  
Manshi Wang ◽  
Yanfeng Li
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Dopaminergic Neurons ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Control Group ◽  
Mitochondrial Morphology ◽  
Cognitive Symptoms

BackgroundAggregation and neurotoxicity of the presynaptic protein α-synuclein and the progressive loss of nigral dopaminergic neurons are believed to be the key hallmarks of Parkinson’s disease (PD). A53T mutant α-synuclein causes early onset PD and more severe manifestations. A growing body of evidence shows that misfolding or deposition of α-synuclein is linked to the maintenance of mitochondrial dynamics, which has been proven to play an important role in the pathogenesis of PD. It has been observed that Dl-3-n-butylphthalide (NBP) may be safe and effective in improving the non-tremor-dominant PD. However, the potential mechanism remains unclear. This study aimed to investigate whether NBP could decrease the loss of dopaminergic neurons and α-synuclein deposition and explore its possible neuroprotective mechanisms.MethodsA total of 20 twelve-month-old human A53T α-synuclein transgenic mice and 10 matched adult C57BL/6 mice were included in the study; 10 adult C57BL/6 mice were selected as the control group and administered with saline (0.2 ml daily for 14 days); 20 human A53T α-synuclein transgenic mice were randomly divided into A53T group (treated in the same manner as in the control group) and A53T + NBP group (treated with NBP 0.2 ml daily for 14 days). Several markers of mitochondrial fission and fusion and mitophagy were determined, and the behavioral, olfactory, and cognitive symptoms were assessed as well.ResultsIn the present study, it was observed that the A53T-α-synuclein PD mice exhibited anxiety-like behavioral disturbance, impairment of coordination ability, memory deficits, and olfactory dysfunction, loss of dopaminergic neurons, and α-synuclein accumulation. Meanwhile, the mitofusin 1 expression was significantly decreased, and the mitochondrial number and dynamin-related protein 1, Parkin, and LC3 levels were increased. The detected levels of all markers were reversed by NBP treatment, and the mitochondrial morphology was partially recovered.ConclusionIn the present study, a valuable neuropharmacological role of NBP has been established in the A53T-α-synuclein PD mouse model. Possible neuroprotective mechanisms might be that NBP is involved in the maintenance of mitochondrial dynamics including mitochondrial fission and fusion and clearance of damaged mitochondria. It is essential to perform further experiments to shed light on the precise mechanisms of NBP on mitochondrial homeostasis.

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.

scholarly journals SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson’s disease

Brain ◽  
2010 ◽  
Vol 133 (7) ◽  
pp. 2032-2044 ◽  
Author(s):  
Pablo Garcia-Reitböck ◽  
Oleg Anichtchik ◽  
Arianna Bellucci ◽  
Mariangela Iovino ◽  
Chiara Ballini ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Transgenic Mouse Model ◽  
Snare Protein ◽  
Synaptic Failure
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