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Cell sub-issue: The mechanism of running improving Parkinson's disease was discovered for the first time!

 Last Update: 2022-10-21
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Parkinson's disease has become the second largest neurodegenerative disease in the world, and the prevalence is set to double
in the next 30 years.
The surge in the number of cases will pose enormous challenges
to national health systems.

In recent years, thanks to the rapid development of genetic detection technology, imaging technology, artificial intelligence and other technologies, the development of diagnostic biomarkers for Parkinson's disease has made substantial progress [1].

Due to the unclear pathological mechanism of Parkinson's disease, there is still no clinical treatment to delay the neurodegenerative process [2].

Therefore, the development of a treatment that can slow down the neurodegenerative process of Parkinson's disease has become a difficult problem
facing researchers in various countries.

Recently, a research team led by Kalipada Pahan of Rush University Medical Center in the United States published an important research result
in the journal Cell Reports.

For the first time, they discovered that regular running training can delay pathological progression and exercise performance in a mouse model of Parkinson's disease [3].

Specifically, they found that regular running training slowed the spread of α-synuclein (α-syn) in the mouse brains and protected dopaminergic neurons
in the substantia nigra.

Screenshot of the front page of the paper

In a normal brain, α-Syn plays an integral role in vesicle transport and the function of the dopamine transmitter, but α-Syn performs this physiological function only if its quantity and function are normal
.
Once α-Syn is overexpressed and/or mutated, α-Syn gradually forms pathologically oligomeric states
.

As pathological α-syn continues to spread and accumulate in brain areas such as substantia nigra and striatum, nerve cells in the corresponding areas will be overwhelmed and dead, nerve function will be abnormal, and eventually develop into Parkinson's disease [4].

Until now, there was no treatment that could effectively stop the spread
of α-syn in the brain.
Therefore, once Parkinson's disease is suffered, it will always be in a state
of deterioration.

As we all know, regular exercise has many positive effects
on human health.
Running is the easiest form of exercise, and a large number of studies have used running training as one of the rehabilitation programs to improve the exercise ability of patients with neurological disorders to improve exercise capacity [5].

So the researchers focused on whether regular running training had a positive effect on Parkinson's disease
.

Pahan's team noted that previous studies have shown that α-Synon can propagate to the motor cortex, striatum, and substantia nigra (SN) regions after injection of α-synuclein precursor fibrils (PFFs) into the inner capsule (IC) [6].

Therefore, during the experiment, the researchers used brain stereo injection technology to inject PFF into the inner capsule of 2-month-old A53T mice (Parkinson's disease model mice), allowing α-Syn to spread
naturally in the brains of A53T mice for two months.

Subsequently, the researchers randomly divided all the mice into two groups, one group for two months of treadmill training, training frequency 30min a day, 6 days a week; The other group did not train for running as a control group
.
Histological and behavioral testing
is performed two months later.

Experimental design of running training

The researchers first subjected immunohistochemical staining
of α-Synon and phosphorylated synuclein (pSyn129) in the substantia nigra region.

The results showed that compared with A53T mice (A53T + PFF NR) in the running training group (A53T + PFF NR), the insoluble pathological α-Syn in the substantia nigra region of the A53T group (A53T + PFF R) in the running training group was significantly reduced
.
In addition, the pSyn129 content in the substantia nigra region was also significantly reduced
.

The above experimental results show that running training can inhibit the pathological transmission
of α-Syn in the substantia nigra of A53T mice.

At the same time, the researchers performed immunohistochemical staining on
dopaminergic neurons in the substantia nigra region and tyrosine hydroxylase (TH), which catalyzes the production of dopamine (DA).

The staining results showed that compared with the A53T mice (A53T+PFF NR) in the running training group, the loss of dopaminergic neurons and tyrosine hydroxylase in the substantia nigra region of the A53T group (A53T+PFF R) in the running training group was significantly reduced
.

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Next, the researchers further tested
the dopamine content, intermediates, and tyrosine hydroxylase levels.

The results showed that with the protection of dopaminergic neurons, the loss of dopamine, tyrosine hydroxylase and intermediate products 3,4-dihydroxyphenylacetic acid (DOPAC) and high vanillic acid (HVA) in the regular running training group was also significantly reduced
.

The researchers then performed behavioral tests
on the mice's ability to exercise.

The results of the open field experiment showed that the exercise ability of mice in the A53T group (A53T+PFF R) in the running training group was significantly improved
.

Open field experiments

The above experimental results show that regular running training has a significant protective effect
on dopaminergic neurons in the substantia nigra region of A53T mice.

After observing that regular running training has a protective effect on the pathological transmission of α-Syn in the brain of A53T mice, the researchers decided to further explore
the mechanism.

In the aforementioned study, Pahan's team found that exercise leads to a reduction in insoluble pathological α-Syn content, suggesting that autophagy and lysosomal protein degradation pathways may be one of
the main mechanisms by which running training promotes the degradation of misfolded protein aggregates.

Therefore, they consulted a large amount of literature for clues
.
Pahan's team noted that previous studies have shown that PPARα protein plays an important role in lysosomal production and autophagy pathways, and studies have shown that PPARα protein levels in skeletal muscle are significantly increased
after running training.

Based on the above research results, the researchers decided to carry out mechanism research
around PPARα protein.
Studies have confirmed that the level of PPARα protein in the substantia nigra region of the A53T group (A53T + PFF R) mice in the running training group is indeed significantly increased
.

PPARα immunofluorescence staining in SN regions

Next, the researchers obtained offspring mice (A53T△PPARα) that lacked PPARα protein and overexpressed α-Syn by crossing PPARα-/^- homozygous mice with A53T homozygous mice with A53T homozygous mice, and further verified that the lack of ^PPARα protein in vivo could not exert a protective effect
even if the mice were trained for the same running.

The results confirmed that compared with the running training group (A53T+PFF R) with normal PPARα protein, the content of pSyn129 and insoluble pathological α-Syn in the substantia nigra region of the running training group (A53T^△PPARα+PFF R) lacking PPARα protein was significantly increased
.

These results suggest that PPARα protein is key to
slowing the pathological spread of α-syn in running training.

Immunohistochemical staining

Finally, the researchers tried to give mice the PPARα agonist Fenofibrate to see if it could exert a protective effect
similar to running training.

The results confirmed that the content of pSyn129 and insoluble pathological α-Syn in the substantia nigra region of mice in the Fenofibrate group (A53T + PFF + Feno) was significantly reduced, and the loss of tyrosine hydroxylase neurons and tyrosine hydroxylase was significantly reduced
.

At the same time, the open field experiment and the rotary rod experiment on mice also showed that the exercise ability was improved
after the use of Fenofibrate.

These results confirm that mice using PPARα agonists are able to delay the pathological spread of α-Syno and protect tyrosine hydroxylase neurons
.

Overall, running training or drug-mediated PPARα activation may help prevent α-Syn pathological spread and related neuronal degeneration
.
The Pahan team's study offers new hope
for patients with Parkinson's disease and other neurodegenerative diseases to delay progression and improve their quality of life.

References:

[1].
Tolosa E, Garrido A, Scholz SW, Poewe W.
Challenges in the diagnosis of Parkinson's disease.
Lancet Neurol.
2021; 20（5):385-397.
doi:10.
1016/S1474-4422（21)00030-2

[2].
Kalia LV, Lang AE.
Parkinson's disease.
Lancet.
2015; 386（9996):896-912.
doi:10.
1016/S0140-6736（14)61393-3

[3].
Dutta D, Paidi RK, Raha S, Roy A, Chandra S, Pahan K.
Treadmill exercise reduces α-synuclein spreading via PPARα.
Cell Rep.
2022; 40(2):111058.
doi:10.
1016/j.
celrep.
2022.
111058

[4].
Hofer A, Berg D, Asmus F, et al.
The role of alpha-synuclein gene multiplications in early-onset Parkinson's disease and dementia with Lewy bodies.
J Neural Transm （Vienna).
2005; 112（9):1249-1254.
doi:10.
1007/s00702-004-0263-3

[5].
Minakaki G, Canneva F, Chevessier F, et al.
Treadmill exercise intervention improves gait and postural control in alpha-synuclein mouse models without inducing cerebral autophagy.
Behav Brain Res.
2019; 363:199-215.
doi:10.
1016/j.
bbr.
2018.
11.
035

[6].
Sorrentino ZA, Brooks MMT, Hudson V 3rd, et al.
Intrastriatal injection of α-synuclein can lead to widespread synucleinopathy independent of neuroanatomic connectivity.
Mol Neurodegener.
2017; 12(1):40.
Published 2017 May 29.
doi:10.
1186/s13024-017-0182-z

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