Acupuncture Inhibits the Increase in Alpha-Synuclein by Modulating SGK1 in an MPTP Induced Parkinsonism Mouse Model

2019 ◽  
Vol 47 (03) ◽  
pp. 527-539
Author(s):  
Sujung Yeo ◽  
Sabina Lim
Keyword(s):  
Mouse Model ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Cell Loss ◽  
Alpha Synuclein ◽  
Control Group ◽  
Dystrophic Neurites ◽  
Dopaminergic Cell ◽  
Acupuncture Stimulation

Parkinson’s disease (PD), a progressive neurodegenerative disease, is caused by the loss of dopaminergic neurons in the substantia nigra (SN). It is characterized by the formation of intracytoplasmic Lewy bodies that are primarily composed of the protein alpha-synuclein ([Formula: see text]-syn) along with dystrophic neurites. Acupuncture stimulation results in an enhanced survival of dopaminergic neurons in the SN in parkinsonism animal models. We investigated the role of acupuncture in inhibiting the increase in [Formula: see text]-syn expression that is related with dopaminergic cell loss in the SN in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonism mouse model. In this model, acupuncture stimulation at GB34 and LR3 attenuated the decrease in tyrosine hydroxylase. Moreover, acupuncture stimulation attenuated the increase in [Formula: see text]-syn. We identified that serum- and glucocorticoid-dependent kinase 1 (SGK1) is evidently downregulated in chronic MPTP-intoxication and acupuncture stimulation maintained SGK1 expression at levels similar to the control group. For an examination of the expression correlation between SGK1 and [Formula: see text]-syn, SH-SY5Y cells were knocked down with SGK1 siRNA then, the downregulation of dopaminergic cells and the increase in the expression of [Formula: see text]-syn were observed. Our findings indicate that the acupuncture-mediated inhibition in the [Formula: see text]-syn increase induced by MPTP may be responsible for modulating SGK1 expression.

scholarly journals Association Between Decreased Srpk3 Expression And An Increase In Substantia Nigra Alpha-Synuclein Levels In An MPTP-Induced Parkinson’s Disease Mouse Model

2022 ◽  
Author(s):  
Min Hyung Seo ◽  
Sujung Yeo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Cell Loss ◽  
Alpha Synuclein ◽  
Mice Model ◽  
Dopaminergic Cell ◽  
The Brain

Abstract Parkinson’s disease (PD) is known as the second most common neurodegenerative disease, which is caused by destruction of dopaminergic neurons in the substantia nigra (SN) of the brain; however, the reason for the death of dopaminergic neurons remains unclear. An increase in α-synuclein (α-syn) is considered an important factor in the pathogenesis of PD. In the current study, we investigated the association between PD and serine/arginine-rich protein specific kinase 3 (Srpk3) in MPTP-induced parkinsonism mice model and in SH-SY5Y cells treated with MPP+. Srpk3 expression was significantly downregulated, while tyrosine hydroxylase (TH) decreased and α-synuclein (α-syn) increased after 4 weeks of MPTP intoxication treatment. Dopaminergic cell reduction and α-syn increase were demonstrated by inhibiting Srpk3 expression by siRNA in SH-SY5Y cells. Moreover, a decrease in Srpk3 expression upon siRNA treatment promoted dopaminergic cell reduction and α-syn increase in SH-SY5Y cells treated with MPP+. These results suggest that the decrease in Srpk3 expression due to Srpk3 siRNA caused both a decrease in TH and an increase in α-syn. This raises new possibilities for studying how Srpk3 controls dopaminergic cells and α-syn expression, which may be related to the pathogenesis of PD. Our results provide an avenue for understanding the role of Srpk3 during dopaminergic cell loss and α-syn increase in the SN. Furthermore, this study could support a therapeutic possibility for PD in that the maintenance of Srpk3 expression inhibited dopaminergic cell reduction.

scholarly journals Genetic inactivation of alpha-synuclein affects embryonic development of dopaminergic neurons of the substantia nigra, but not the ventral tegmental area, in mouse brain

2018 ◽  
Author(s):  
Tatiana V Tarasova ◽  
Olga A Lytkina ◽  
Valeria V Goloborshcheva ◽  
Larisa N Skuratovskaya ◽  
Alexandr I Antohin ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Embryonic Development ◽  
Ventral Tegmental Area ◽  
Knockout Mice ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Nigrostriatal System ◽  
Ventral Tegmental

Lesion of the dopaminergic neurons of the nigrostriatal system is a key feature of Parkinson's disease (PD). Alpha-synuclein is a protein that is a major component of Lewy bodies, histopathological hallmarks of PD, and is involved in regulation of dopamine (DA) neurotransmission. Previous studies of knockout mice have shown that inactivation of alpha-synuclein gene can lead to the reduction in number of DA neurons in the substantia nigra (SN). DA neurons of the SN are known to be the most affected in PD patients whereas DA neurons of neighboring ventral tegmental area (VTA) are much less susceptible to degeneration. Here we have studied the dynamics of changes in TH-positive cell numbers in the SN and VTA during a critical period of their embryonic development in alpha-synuclein knockout mice. This precise study of DA neurons during development of the SN revealed that not only is the number of DA neurons reduced by the end of the period of ontogenic selection, but that the way these neurons are formed is altered in alpha-synuclein knockout mice. At the same time, DA neurons in the VTA are not affected. Alpha-synuclein exerts a modulating effect on the formation of DA neurons in the SN and has no effect on the formation of DA neurons in VTA, the structure that is much less susceptible to degeneration in PD brain, suggesting a potential role of alpha-synuclein in the development of the population of DA neurons in substantia nigra.

scholarly journals Genetic inactivation of alpha-synuclein affects embryonic development of dopaminergic neurons of the substantia nigra, but not the ventral tegmental area, in mouse brain

2018 ◽  
Author(s):  
Tatiana V Tarasova ◽  
Olga A Lytkina ◽  
Valeria V Goloborshcheva ◽  
Larisa N Skuratovskaya ◽  
Alexandr I Antohin ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Embryonic Development ◽  
Ventral Tegmental Area ◽  
Knockout Mice ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Nigrostriatal System ◽  
Ventral Tegmental

Lesion of the dopaminergic neurons of the nigrostriatal system is a key feature of Parkinson's disease (PD). Alpha-synuclein is a protein that is a major component of Lewy bodies, histopathological hallmarks of PD, and is involved in regulation of dopamine (DA) neurotransmission. Previous studies of knockout mice have shown that inactivation of alpha-synuclein gene can lead to the reduction in number of DA neurons in the substantia nigra (SN). DA neurons of the SN are known to be the most affected in PD patients whereas DA neurons of neighboring ventral tegmental area (VTA) are much less susceptible to degeneration. Here we have studied the dynamics of changes in TH-positive cell numbers in the SN and VTA during a critical period of their embryonic development in alpha-synuclein knockout mice. This precise study of DA neurons during development of the SN revealed that not only is the number of DA neurons reduced by the end of the period of ontogenic selection, but that the way these neurons are formed is altered in alpha-synuclein knockout mice. At the same time, DA neurons in the VTA are not affected. Alpha-synuclein exerts a modulating effect on the formation of DA neurons in the SN and has no effect on the formation of DA neurons in VTA, the structure that is much less susceptible to degeneration in PD brain, suggesting a potential role of alpha-synuclein in the development of the population of DA neurons in substantia nigra.

Does human alpha synuclein behave like prions?

2021 ◽  
Vol 20 ◽  
Author(s):  
Yasir Hasan Siddique
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Synaptic Vesicles ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Present Review ◽  
Exact Role

: Alpha synuclein (α-synuclein) is a protein which is abundantly found in brain and in lesser amount in heart and muscles. The exact role of α-synuclein is not known but it is consider to control the movement of synaptic vesicles. Its overexpression in the neurons leads to the formation of Lewy bodies which specifically damage the dopaminergic neurons in the subtantianigra of the mid brain and leads to the progression of Parkinson’s disease (PD). There are evidences that aggregates of α-synuclein behaves like prions. The present review is an attempt to put forth the nature of α-synuclein as prions.

scholarly journals Genetic inactivation of alpha-synuclein affects embryonic development of dopaminergic neurons of the substantia nigra, but not the ventral tegmental area, in mouse brain

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4779 ◽  
Author(s):  
Tatiana V. Tarasova ◽  
Olga A. Lytkina ◽  
Valeria V. Goloborshcheva ◽  
Larisa N. Skuratovskaya ◽  
Alexandr I. Antohin ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Embryonic Development ◽  
Ventral Tegmental Area ◽  
Knockout Mice ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Nigrostriatal System ◽  
Ventral Tegmental

Lesion of the dopaminergic neurons of the nigrostriatal system is a key feature of Parkinson’s disease (PD). Alpha-synuclein is a protein that is a major component of Lewy bodies, histopathological hallmarks of PD, and is involved in regulation of dopamine (DA) neurotransmission. Previous studies of knockout mice have shown that inactivation of alpha-synuclein gene can lead to the reduction in number of DA neurons in the substantia nigra (SN). DA neurons of the SN are known to be the most affected in PD patients whereas DA neurons of neighboring ventral tegmental area (VTA) are much less susceptible to degeneration. Here we have studied the dynamics of changes in TH-positive cell numbers in the SN and VTA during a critical period of their embryonic development in alpha-synuclein knockout mice. This precise study of DA neurons during development of the SN revealed that not only is the number of DA neurons reduced by the end of the period of ontogenic selection, but that the way these neurons are formed is altered in alpha-synuclein knockout mice. At the same time, DA neurons in the VTA are not affected. Alpha-synuclein exerts a modulating effect on the formation of DA neurons in the SN and has no effect on the formation of DA neurons in VTA, the structure that is much less susceptible to degeneration in a brain with PD, suggesting a potential role of alpha-synuclein in the development of the population of DA neurons in substantia nigra.

scholarly journals Alpha-Synuclein RNA Expression is Increased in Major Depression

2019 ◽  
Vol 20 (8) ◽  
pp. 2029 ◽  
Author(s):  
Andrea Rotter ◽  
Bernd Lenz ◽  
Ruben Pitsch ◽  
Tanja Richter-Schmidinger ◽  
Johannes Kornhuber ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Control Group ◽  
Expression Levels ◽  
Healthy Control ◽  
Severity Of Depression ◽  
High Comorbidity ◽  
Mrna Expression Levels

Alpha-synuclein (SNCA) is a small membrane protein that plays an important role in neuro-psychiatric diseases. It is best known for its abnormal subcellular aggregation in Lewy bodies that serves as a hallmark of Parkinson’s disease (PD). Due to the high comorbidity of PD with depression, we investigated the role of SNCA in patients suffering from major depressive disorder (MDD). SNCA mRNA expression levels were analyzed in peripheral blood cells of MDD patients and a healthy control group. SNCA mRNA expression was positively correlated with severity of depression as indicated by psychometric assessment. We found a significant increase in SNCA mRNA expression levels in severely depressed patients compared with controls. Thus, SNCA analysis could be a helpful target in the search for biomarkers of MDD.

scholarly journals 14-3-3 mitigates alpha-synuclein aggregation and toxicity in the in vivo preformed fibril model

2020 ◽  
Author(s):  
Rachel Underwood ◽  
Mary Gannon ◽  
Aneesh Pathak ◽  
Navya Kapa ◽  
Sidhanth Chandra ◽  
...  
Keyword(s):  
Social Dominance ◽  
Lewy Bodies ◽  
Neuronal Loss ◽  
Cell Loss ◽  
Brain Regions ◽  
Alpha Synuclein ◽  
Dopaminergic Cell ◽  
The Impact

AbstractAlpha-synuclein (αsyn) is the key component of proteinaceous aggregates termed Lewy Bodies (LBs) that pathologically define a group of disorders known as synucleinopathies, including Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB). αSyn is hypothesized to misfold and spread throughout the brain in a prion-like fashion. Transmission of αsyn necessitates the release of misfolded αsyn from one cell and the uptake of that αsyn by another, in which it can template the misfolding of endogenous αsyn upon cell internalization. 14-3-3 proteins are a family of highly expressed brain proteins that are neuroprotective in multiple PD models. We have previously shown that 14-3-3θ acts as a chaperone to reduce αsyn aggregation, cell-to-cell transmission, and neurotoxicity in the in vitro pre-formed fibril (PFF) model. In this study, we expanded our studies to test the impact of 14-3-3s on αsyn toxicity in the in vivo αsyn PFF model. We used both transgenic expression models and adenovirus associated virus (AAV)-mediated expression to examine whether 14-3-3 manipulation impacts behavioral deficits, αsyn aggregation, and neuronal loss in the PFF model. 14-3-3θ transgene overexpression in cortical and amygdala regions rescued social dominance deficits induced by PFFs at 6 months post injection, whereas 14-3-3 inhibition by transgene expression of the competitive 14-3-3 peptide inhibitor difopein in the cortex and amygdala accelerated social dominance deficits. The behavioral rescue by 14-3-3θ overexpression was associated with delayed αsyn aggregation induced by PFFs in these brain regions. Conversely, 14-3-3 inhibition by difopein in the cortex and amygdala accelerated αsyn aggregation and cortical pyramidal neuron loss induced by PFFs. 14-3-3θ overexpression by AAV in the substantia nigra (SN) also delayed αsyn aggregation in the SN and partially rescued PFF-induced dopaminergic cell loss in the SN. 14-3-3 inhibition in the SN accelerated nigral αsyn aggregation and increased PFF-induced dopaminergic cell loss. These data indicate a neuroprotective role for 14-3-3θ against αsyn toxicity in vivo.

scholarly journals Genetic inactivation of alpha-synuclein affects embryonic development of dopaminergic neurons of the substantia nigra but not the ventral tegmental area in mouse brain

2018 ◽  
Author(s):  
Tatyana V Tarasova ◽  
Olga A Lytkina ◽  
Valeria V Goloborshcheva ◽  
Larisa N Skuratovskaya ◽  
Alexandr I Antohin ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Embryonic Development ◽  
Ventral Tegmental Area ◽  
Knockout Mice ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Nigrostriatal System ◽  
Ventral Tegmental

Lesion of the dopaminergic neurons of the nigrostriatal system is a key feature of Parkinson's disease (PD). Alpha-synuclein is a protein that is a major component of Lewy bodies, histopathological hallmarks of PD, and is involved in regulation of dopamine (DA) neurotransmission. Previous studies of knockout mice have shown that inactivation of alpha-synuclein gene can lead to the reduction in number of DA neurons in the substantia nigra (SN). DA neurons of the SN are known to be the most affected in PD patients whereas DA neurons of neighboring ventral tegmental area (VTA) are much less susceptible to degeneration. Here we have studied the dynamics of changes in TH-positive cell numbers in the SN and VTA during a critical period of their embryonic development in alpha-synuclein knockout mice. This precise study of DA neurons during development of the SN revealed that not only is the number of DA neurons reduced by the end of the period of ontogenic selection, but that the way these neurons are formed is altered in alpha-synuclein knockout mice. At the same time, DA neurons in the VTA are not affected. Alpha-synuclein exerts a modulating effect on the formation of DA neurons in the SN and has no effect on the formation of DA neurons in VTA, the structure that is much less susceptible to degeneration in PD brain, suggesting a potential role of alpha-synuclein in the development of the population of DA neurons in substantia nigra.

scholarly journals Neurons and Glia Interplay in α-Synucleinopathies

2021 ◽  
Vol 22 (9) ◽  
pp. 4994
Author(s):  
Panagiota Mavroeidi ◽  
Maria Xilouri
Keyword(s):  
Glial Cells ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Lewy Neurites ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Glial Function ◽  
Presynaptic Protein

Accumulation of the neuronal presynaptic protein alpha-synuclein within proteinaceous inclusions represents the key histophathological hallmark of a spectrum of neurodegenerative disorders, referred to by the umbrella term a-synucleinopathies. Even though alpha-synuclein is expressed predominantly in neurons, pathological aggregates of the protein are also found in the glial cells of the brain. In Parkinson’s disease and dementia with Lewy bodies, alpha-synuclein accumulates mainly in neurons forming the Lewy bodies and Lewy neurites, whereas in multiple system atrophy, the protein aggregates mostly in the glial cytoplasmic inclusions within oligodendrocytes. In addition, astrogliosis and microgliosis are found in the synucleinopathy brains, whereas both astrocytes and microglia internalize alpha-synuclein and contribute to the spread of pathology. The mechanisms underlying the pathological accumulation of alpha-synuclein in glial cells that under physiological conditions express low to non-detectable levels of the protein are an area of intense research. Undoubtedly, the presence of aggregated alpha-synuclein can disrupt glial function in general and can contribute to neurodegeneration through numerous pathways. Herein, we summarize the current knowledge on the role of alpha-synuclein in both neurons and glia, highlighting the contribution of the neuron-glia connectome in the disease initiation and progression, which may represent potential therapeutic target for a-synucleinopathies.

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