Astaxanthin and Parkinson’s disease (PD)

Astaxanthin suppresses endoplasmic reticulum stress and protects against neuron damage in Parkinson’s disease by regulating miR-7/SNCA axis

Dong-Fang ShenHui-Ping QiChi Ma Ming-Xiu Chang Wei-Na Zhang Rong-Rong

Song Department of Neurology, The Fourth Clinical College of Harbin Medical University, Harbin, 150001, PR China

Received 9 January 2020, Revised 19 March 2020, Accepted 15 April 2020, Available online 22 April 2020.


disease (PD) is a common neurodegenerative disorder that featured by
the loss of dopaminergic neurons. Astaxanthin (AST), an important
antioxidant, is demonstrated to be a neuroprotective agent for PD.
However, the underlying mechanisms of AST in PD remain largely unclear.
In this study, we found that AST treatment significantly not only
abolished the cell viability inhibition and apoptosis promotion induced
by 1-methyl-4-phenylpyridinium (MPP+) in SH-SY5Y cells via inhibiting
endoplasmic reticulum (ER) stress, but also reversed the MPP+ caused
dysregulation of miR-7 and SNCA expression. MiR-7 knockdown and SNCA
overexpression were achieved by treating SH-SY5Y cells with miR-7
inhibitor and pcDNA3.1-SNCA plasmids, respectively. MiR-7 could bind to
and negatively regulate SNCA in SH-SY5Y cells. Treated SH-SY5Y cells
with miR-7 inhibitor or pcDNA3.1-SNCA abrogated the protective effects
of AST on MPP+ induced cytotoxicity. Knockdown of miR-7 aggravated
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neuron
injury in vivo suggested by athletic performance,
histopathological morphology, expression of tyrosine hydroxylase (TH)
and TUNEL positvie cells, however, AST treatment could reverse these
effects of miR-7 knockdown. Collectively, AST suppressed ER stress
and protected against PD-caused neuron damage by targeting miR-7/SNCA
axis, implying that AST might be a potential effective therapeutic agent
for PD.



disease (PD) currently ranks as the second progressive
neurodegenerative disorder in the world, influencing more than 2% of the
population over 60-years old (Kalia and Lang, 2015). Its clinical
manifestation mainly includes rest tremor, bradykinesia, muscular
rigidity, postural and gait impairment (Opara et al., 2017, Schneider et
al., 2017). The selective absence of dopaminergic neurons in substantia
nigra (SN) area is the hallmark of PD, which caused a substantial
decrease of dopamine in the striatum (Liu et al., 2019). Although it
remains largely undetermined, the etiology of PD was found to be closely
correlated with a number of risk factors including age, endoplasmic
reticulum (ER) stress, functional disturbance of mitochondrial, gender
and external toxins (Ascherio and Schwarzschild, 2016). The world
prevalence of PD and the economic burden caused by PD are predicted to
increase dramatically (Delamarre and Meissner, 2017). The current
pharmacological interventions mainly alleviate motor symptoms, while the
debilitating non-motor symptoms still impair the life quality of PD
patients (Orimo, 2017). Up to now, no effective therapeutic measures
could be available to conquer the neurodegeneration or restore the loss
of dopaminergic neurons in SN (Schneider et al., 2017). Therefore,
exploring more effective agents remain a primary and unfulfilled goal of
PD therapy. Elucidating the underlying mechanisms of PD pathogenesis
might be contributed to achieve this goal.

(miRNAs) are a class of small non-coding RNAs with approximately 22
nucleotides in length without protein-coding ability and once considered
to be useless in the normal biological processes (Bartel, 2004, Krol et
al., 2010). However, with developing of the related researches, miRNAs
have been shown to possess a close association with the critical factors
involving the translational machinery, and thus play an important role
during the degeneration and transcription of mRNA (Ameres and Zamore,
2013). The association between miRNAs expression level in the nervous
system and neurodegenerative diseases has been revealed via the
regulation of the translation of target genes (Qiu et al., 2015).
Numerous of miRNAs were identified to affect the onset and development
of PD through multiple distinct mechanisms (Martinez and Peplow, 2017).
Alpha synuclein (SNCA), a key component of Lewy bodies (a
neuropathological hallmark of PD), is deemed to be a major causative
gene that responsible for the onset of familial PD (Siddiqui et al.,
2016). Previous studies have demonstrated that the aggregation of SNCA
might be correlated with miRNAs dysregulation. For example, miR-16-1 was
verified to promote SNCA accumulation in PD by targeting heat shock
protein 70 (Zhang and Cheng, 2014). MiR-7 was revealed to be decreased
in PD, and its absence in vivo resulted in a dopaminergic
neuronal loss and accumulation of SNCA (Choi et al., 2018). However,
whether miR-7 involves in PD development by directly targeting with SNCA
remains undetermined.

Interestingly, many compounds
have been found to possess the neuroprotective properties and might be
developed into effective agents for the clinical therapy of
neurodegeneration diseases (Grimmig et al., 2018). Among these
compounds, astaxanthin (AST) is predicted to be one of the most
promising agent for PD treatment (Fakhri et al., 2019). AST is a
carotenoid that mainly exists in several microorganisms with strong
antioxidant and anti-inflammatory properties (Fakhri et al., 2019). It
has a powerful protective effect on human central nervous system against
PD by reducing the oxidative stress in neuronal cell (Galasso et al.,
2018, Lin and Beal, 2006), but whether through suppressing ER stress
remains unclear. Recently, AST was found to affect cell growth and
apoptosis by regulating miRNA expression (Ni et al., 2017, Zhu et al.,
2019), however, there is no report on the correlation between AST and
miRNAs in PD pathogenesis.

Our bioinformatics
analysis predicted that SNCA might be the target of miR-7. Therefore, in
this study, we aimed to study whether the protective effects of AST
against PD induced neuron injury in vitro and in vivo through ER stress inhibition are mediated by miR-7/SNCA axis.

Section snippets

Cell culture and treatment

neuroblastoma SH-SY5Y cell line was obtained from Cell bank of Chinese
Academy of Sciences (Shanghai, China) and maintained in the DMEM
containing 10% fetal calf serum in a cell incubator filled with 5% CO2.
For drug treatment, SH-SY5Y cells were seeded into plates and cultured
at 37 ℃ overnight, then cells were incubated with various concentrations
of MPP+ or AST for 24 h.

Cell transfection

miR-7 mimics (5’-UGGAAGACUAGUGAUUUUGUUGUU-3’), miR-7 inhibitor (5’-AACAACAAAAUCACUAGUCUUCCA-3’) and their negative

AST abrogates the SH-SY5Y cell injury caused by MPP+

has been shown to induce a syndrome closely resembling PD model by
initiating neuron cell death. To further support this conclusion, we
treated SH-SY5Y cells with different concentrations of MPP+ (125, 250,
500, 1000, 2000 and 4000 μM) followed by the MTT analysis of cell
viability. Compared to untreated control group, the cell viability of
MPP+ treated SH-SY5Y cells were significantly decreased (Fig. 1A). Moreover, after MPP+ treatment, some morphological changes were observed in SH-SY5Y


currently develops into the second most frequent neurodegenerative
disorder after Alzheimer’s disease, causing great psychological and
financial pressure on patients (Gasser et al., 2011). PD mainly occurs
in the elderly population that over 60-years old, and only a small
proportion of patients (approximately 5%) are diagnosed before the age
of 60-years (Reeve et al., 2014). With the coming of aging society, the
number of PD patients is expected to be rapidly increase in the further

Declaration of Competing Interest

The authors have no commercial or other associations that might pose a conflict of interest.


This work was supported by Funding for postdoctoral support in Heilongjiang Province (No. LBH-Z18189) and the Fundamental Research Funds for the Provincial Universities (2019-KYYWF-0365).


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