For informational purposes only
Alpha Synuclein
1. INTRODUCTION:
There are no effective treatments nor drugs available to modify disease progression in people suffering with Parkinson’s disease. Increasing experimental evidence suggests a causal relationship between alpha-synuclein (α-synuclein, α-syn), a renegade protein and the complex neuropathology of Parkinson’s diseases. Although the exact pathophysiological role of α-synuclein in the disease is currently not completely understood. 1
Neuroinflammation, oxidative stress, and protein misfolding, aggregation as well as cell-to-cell spread of malformed a-synuclein contribute to a vicious cycle in the pathophysiology of Parkinson's disease (PD); with activated microglia as the main source of neuroinflammation. 2
Therapeutic options for Parkinson’s disease (PD) are limited to a symptomatic approach. Whereas attempts at modulating neurodegenerative mechanisms like aggregated alpha-synuclein (α-syn) clearance by promoting autophagy, 3 disrupting α-synuclein aggregation, suppressing inflammasome activation, and inhibiting apoptosis or programmed cell death in the nigrostriatal dopaminergic system of animal models of PD are under investigation. 2
In many ways, research is suggesting that a-synuclein exhibits characteristics of a Prion protein. Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal isoform of the protease-insensitive isoform (PrPSc) of prion protein. The human prion protein fragments PrP106‑126, contain most of the abnormal characteristics associated with the disease producing PrPSc, segment. 4
Let’s examine some of the similarities shared between a-syn and disease producing prion proteins.
2. FIBRILLS/AGGREATION:
Parkinson's disease (PD) is the second most common neurodegenerative diseases with no curative treatment yet available. Its major hallmark is α-synuclein fibrillary aggregates. The crucial role of α-synuclein aggregation in PD makes this protein an attractive target for potential disease-modifying therapies. 5
Treatments that disaggregate α-synuclein fibrils are considered some of the more promising therapeutic strategies under development to treat PD. 5
Recent studies revealed that the oligomeric form of aggregates is most likely the toxic species, and thus could be a good therapeutic target. To screen for potent inhibitors that can inhibit both oligomerisation and fibrillation of α-synuclein (α-syn), researchers systematically compared the antioligomeric and antifibrillar activities of eight compounds 6
Results revealed that baicalein, a flavonoid extracted from the Chinese herbal medicine Scutellaria baicalensis is a potent inhibitor of α-syn oligomerisation both in cell-free and cellular systems, and is also an effective inhibitor of α-syn fibrillation in cell-free systems. 6
Investigators further tested the protective effect of baicalein against α-syn-oligomer-induced toxicity in neuronal cells. There data showed that baicalein inhibited the formation of α-syn oligomers in SH-SY5Y and Hela cells, and protected SH-SY5Y cells from α-syn-oligomer-induced toxicity. 6
Baicalein (BAI), the flavonoid from Chinese herb, has been reported to bind covalently to α-syn to inhibit α-syn fibrillation and degrade its fibrils. However, whether BAI inhibits α-syn secretion is unclear. 7
Aggregation of alpha-synuclein (α-SN) is a key pathogenic event in Parkinson's disease (PD) leading to dopaminergic degeneration. 8
Different Scutellaria species are known as valuable medicinal plants, primarily due to their high flavonoid levels. we report that S. pinnatifida extracts have an anti-fibrillation effect on α-SN aggregation and neuroprotective properties on PC12 and primary dopaminergic neurons. Treatment during α-SN fibril formation with S. pinnatifida extracts showed that the extractions performed with dichloromethane (DCMEx) and n-butanol (BuOHEx) strongly inhibited α-SN fibrillation. 8
Our results showed the extracts strongly protected against α-SN oligomers. Surprisingly, they also neutralized the severe toxicity of paraquat. Therefore, S. pinnatifida may be a potential valuable medicinal herb for further studies related to the treatment of PD. 8
Baicalein, a typical flavonoid compound, can inhibit the formation of the α-syn oligomers, and disaggregate existing α-syn oligomers in vitro. However, whether baicalein could inhibit or disaggregate α-syn oligomers in vivo has not been investigated. 9
Here, preformed fibrillar form (PFF) of α-syn was used to induce PD in wistar rats, which were thereafter subjected to treatment with trehalose (tre, 4g/kg, orally), a potent autophagy inducer and sodium butyrate (SB, 300 mg/kg, orally), a pan histone deacetylase inhibitor alone as well as in combination. 3
Immunofluorescence and H&E staining in the substantia nigra region mirrored a potential improvement after treatment with both tre and SB. Therefore, outcomes of the present study were adequate to prove that combinatorial efficacy with tre and SB may prove to be a formidable insight into ameliorating PD exacerbated by PFF α-syn as compared to its individual efficacy. 3
Transmissible spongiform encephalopathies (TSE) are characterized by the misfolding of the host encoded prion protein (PrP(C)) into a pathogenic isoform (PrP(Sc)) which leads to the accumulation of β-sheet-rich fibrils and subsequent loss of neurons and synaptic functions. Although many compounds have been identified which inhibit accumulation or dissolve fibrils and aggregates in vitro there is no therapeutic treatment to stop these progressive neurodegenerative diseases. 10
ECH, from cistanche, rescued cell viability in damaged cells and decreased 6-OHDA-induced reactive oxygen species accumulation in vitro. It also rescued tyrosine hydroxylase and dopamine transporter expression in the striatum, and decreased a-synuclein aggregation following 6-OHDA treatment in vivo. 11
In 10-month-old APP Tg mice, αsynuclein expression was increased, and the expression of Parkin, UCH-L1, and HSP70 was decreased in the hippocampus. Intragastrical administration of icariin for 6 months decreased α-synuclein expression and increased the expression parkin, UCH-L1, and HSP70 in the hippocampus of APP Tg mice. 12
Incubation of icariin (40 and 80 μM) with A53T α-synuclein-transfected PC12 cells for 24 h showed no difference in the expressions of αsynuclein mRNA among model group and icariin treated groups, but decreased α-synuclein protein expression in both monomer and tetramer. 12
Although a number of compounds have been identified to inhibit PrP accumulation or dissolve fibrils and aggregates in vitro, there is currently no treatment available for these progressive neurodegenerative diseases. 4
Baicalein, the dried root of Scutellaria baicalensis (S. baicalensis) Georgi (known as Huang-qin in traditional Chinese medicine) has been reported to exert neuroprotective effects on neurodegenerative diseases. 4
The wild type (WT) and mutant α-synuclein fibrils exhibit different polymorphs and provide therapeutic targets for PD. Recent experiments reported that a flavonoid baicalein can disrupt WT α-synuclein fibrils. However, the underlying disruptive mechanism remains largely elusive, and whether BAC is capable of disrupting mutant α-synuclein fibrils is also unknown 5
Herein, we performed microsecond molecular dynamics simulations on cryo-EM-determined WT and two familial PD-associated mutant (E46K and H50Q) α-synuclein fibrils with and without baicalein. 5
They found that baicalein destructs WT fibril by disrupting E46-K80 salt-bridge and β-sheets, and by remodeling the inter-protofilament interface. And baicalein can also damage E46K and H50Q mutant fibrils, but to different extents and via different mechanisms. 5
These results reveal that disruptive effects and modes of baicalein on α-synuclein fibrils are polymorphism-dependent. 5
This study suggests that baicalein may be a potential drug candidate to disrupt both WT and E46K/H50Q mutant α-synuclein fibrils and alleviate the pathological process of PD.5
Although baicalein did not decrease α-syn mRNA expression, α-syn oligomers were significantly decreased in the ileum, thoracic spinal cord, and midbrain. Furthermore, transmission electron microscopy analysis showed that baicalein could prevent α-syn monomers from the oligomer formation in vitro. 9
3. Cell-to-Cell spread
Previous studies showed that monomers and polymers of α-synuclein were secreted from damaged nerve cells via exocytosis and occupied healthy nerve cells via endocytosis, which afford evidence for the prion-like role of α-synuclein. 1
The secretion of α-synuclein (α-syn) acts as an essential driver in the propagation of synucleinopathies in brain. The clearance of extracellular α-syn or blockade of the cell-to-cell transmission of α-syn is a promising approach to prohibiting synucleinopathies propagation. 7
In the present study, we investigated the effects of baicalein on the development of prion diseases using cells in vitro. We found that baicalein protected the cells against prion protein ‑induced neuronal cell death by inhibiting the production of reactive oxygen species and mitochondrial dysfunction. We demonstrated that baicalein treatment regulated the phosphorylation of c-Jun N-terminal kinase. 4
Our data suggest that baicalein has potential for use as a therapeutic drug for the treatment of various neurodegenerative diseases, including prion diseases.4
Here we describe the effects of the traditional medicinal herb Scutellaria lateriflora (SL) and its flavonoids compounds baicalein and baicalin, on the development of prion disease using in vitro and in vivo models. 10
S.L extract as well as both constituents reduced the prion protein accumulation in infected cell cultures and cell-free conversion assays and lead to the destabilization of pre-existing prion protein fibrils. 10
Moreover, tea prepared from SL, prolonged significantly the incubation time of infected mice upon oral treatment. Therefore SL extracts as well as the individual compounds can be considered as promising candidates for new therapeutic drugs against prion diseases and neurodegenerative diseases like Parkinson's disease 10
Taken together, baicalein could be a potential drug to inhibit α-syn propagation among the neurons. 7
4. Brain to gut/gut to brain
Aggregation of α-Synuclein is central to the pathogenesis of Parkinson's disease (PD). However, these α-Synuclein inclusions are not only present in brain, but also in gut. 13
Enteroendocrine cells (EECs), which are directly exposed to the gut lumen, can express α-Synuclein and directly connect to α-Synuclein-containing nerves. Dysbiosis of gut microbiota and microbial metabolite short-chain fatty acids (SCFAs) have been implicated as a driver for PD. 13
Short-chain fatty acids (SCFAs) are considered the key molecular link between gut intestinal bacteria (microbiota) and pathogenesis of Parkinson’s disease (PD). However, the role of SCFAs in PD pathogenesis is controversial. 14
5. Dopamine cell biomarkers/ neurodegeneration prevention:
Striatal dopamine levels were measured, systemic administration of baicalein attenuated reductions in striatal dopamine content and tyrosine hydroxylase (a biomarker of dopaminergic neurons) in the infused substantia nigra (SN). Furthermore, elevation in α-synuclein aggregates (a pathological hallmark of PD), ED-1 (a biomarker of activated microglia), activated caspase-1 (a proinflammatory caspase), IL-1β and cathepsin B (a cysteine lysosomal protease) in the infused SN were suppressed in the baicalein-treated rats. 2
Our result showed that the amount of α-syn, changes in the levels of the striatal neurotransmitters, and the behavioral changes found in the chronic PD mouse model were prevented after the baicalein injections. 9
Moreover, we found that baicalein treatment could remarkably protect the synaptic plasticity As traditional dopamine replacement therapy unleashed few effects on depression-like symptom amelioration and synaptic function protection, baicalein might be a more appropriate choice for PD-related depression. The current results suggested that baicalein could act as a treatment for PD-related depression. 15
Low and high doses of NaB significantly increased the content of tyrosine hydroxylase up to 20%, while reducing α-synuclein activation by nearly 160% globally and 133% in the substantia nigra, compared with PD control groups. 16
Here we showed that BAI reduced α-syn in the media of dopaminergic cell lines overexpressing wild-type α-syn (W-syn) or mutant types of α-syn . Increasing the level of macroautophagy. 7
ECH (cistanche)rescued cell viability in damaged cells and decreased 6-OHDA-induced reactive oxygen species accumulation in vitro. It also rescued tyrosine hydroxylase and dopamine transporter expression in the striatum, and decreased a-synuclein aggregation following 6-OHDA treatment in vivo. 11
The validated mechanism of ECH activity was the reduction in the 6-OHDA-induced accumulation of seipin. Seipin has been shown to be a key molecule related to motor neuron disease and was tightly associated with Endoplasmic Reticulum Stress in a number of studies. ECH attenuated neurodegeneration by promoting seipin degradation and relieved Endoplasmic Reticulum Stress. 11
Rats were treated with ROT with a co-administration of Icariin ICA for 5 weeks. Immunohistochemical analysis showed a significant loss in Dopamine neurons in the substantia nigra (SN) of rats treated with ROT, accompanied by an increase in the accumulation of α-synuclein and a compromised mitochondrial respiration. 17
However, co-administration of ICA Icariin potently ameliorated the ROT-induced neuronal cell injury and improved mitochondrial function and decreased the accumulation of αsynuclein. 17
Thus, our results showed that peony extract, paeoniflorin exerts its neuroprotective effect by regulating the α-synuclein/PKC-δ signaling pathway to reduce neuronal apoptosis. 18
6. AUTOPHAGY:
Autophagy is the known mechanism for eukaryotic cells to degrade protein polymers and damaged organelles that proteasome does not cope with. Therefore, promoting the clearance of α-synuclein by enhancing autophagy in neuronal cells could be a promising treatment in the early stage of PD. 1
Autophagy is important for the degradation of α-synuclein, which is critical to the development of PD. However, whether SCFAs can regulate autophagy in PD remains unknown. We aimed to investigate the role of SCFAs and explore the potential mechanisms in rat dopaminergic PC12 cells treated with rotenone. 14
Among the three SCFAs, sodium butyrate (NaB) protected against rotenone-induce
toxicity. NaB activated autophagy pathway and reduced rotenone-induced α-synuclein expression through the activation of autophagy. Notably, NaB activated autophagy pathway through upregulating PGC-1α expression. 14
NaB can protect against rotenone-induced toxicity through activation of the autophagy pathway by upregulating PGC-1α expression via epigenetic modification. 14
Further, mRNA analysis revealed that levels of certain autophagy related genes and proteins implicated in PD pathogenesis significantly improved after administration of both trehalose and Sodium Butyrate. 3
NaB causes α-Synuclein degradation by an Atg5-dependent and PI3K/Akt/mTOR-related autophagy pathway. 13
Whereas ICA (Icariin) also markedly reverses the dysregulation of autophagy caused by ROT in the PC12 cells. Collectively, these results suggest that ICA mediated activation of autophagic flux confers a neuroprotective action on ROT-induced 17
Research shows that rat pheochromocytoma cells (PC12 cells) functionally express acid sensing ion channel (ASICs). ASIC protein expression and its current are regulated by Peony, paeoniflorin. Peony reduces the acidosis-induced accumulation of α-synuclein. Paeoniflorin enhances autophagic degradation of α-synuclein by regulating ASICs.19
7. ER STRESS:
The endoplasmic reticulum (ER) is selectively degraded by ER-phagy to maintain cell homeostasis. α-synuclein accumulates in the ER, causing ER stress that contributes to neurodegeneration in Parkinson's disease (PD), but the role of ER-phagy in α-synuclein modulation is largely unknown. 20
Recent epidemiological studies suggest that echinacoside (ECH), a phenylethanoid glycoside found in Cistanche deserticola, has a protective effect against the development of PD. 11
However, the detailed mechanisms of how ECH suppresses neuronal death have not been fully elucidated. In this study, we confirmed that ECH protects nigrostriatal neurons against 6-hydroxydopamine (6-OHDA)-induced endoplasmic reticulum stress (ERS) in vivo and in vitro. 11
Along with the downregulation of α-synuclein, icariin (40 and 80 μM) elevated the expression of Parkin, UCH-L1, and HSP70 in A53T α-synuclein-transfected cells. 12
Icariin inhibited the over-expression of α-synuclein both in vivo and in vitro. The mechanism of icariin may be related to upregulate Parkin and UCH-L1 expression in ubiquitinproteasome system and HSP70 in molecular chaperone, thus enhancing the degradation of α-synuclein. It is suggested that icariin may have the potential to treat synucleinopathies. Like Parkinson’s Disease. 12
8. Microglia/neuroinflammation:
Sodium Butyrate reached the midbrain Substantia Nigra and attenuated microglia over-activation, decreased the levels of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) and reduced iNOS. 16
The combination (SB + Tre), demonstrated that the levels of pro-inflammatory cytokines were significantly reduced, along with elevated levels of dopamine and histone H3 acetylation. 3
Sodium Butyrate additionally inhibited the activation of pro-inflammatory NF-κB and MAPK signaling pathways in the notable within the region of the SN. Consequently, sodium butyrate could inhibit neuroinflammation and alleviate neurological damage of PD. 16
In addition, peony extract, TGPC improved neurodegeneration, inhibited the excessive activation of microglia and suppressed the production of proinflammatory cytokines induced by MPTP, partially by restoring leucine-rich repeat kinase 2 (LRRK2) activity and inhibiting alpha-synuclein (α-syn) mediated neuroinflammation signaling. 21
The effects of Baicalein given orally for four weeks on behavior, neuroinflammation, neurotransmitters, and synaptic plasticity were evaluated. 15
Our results showed that 4-week baicalein treatment significantly alleviated the depression-like behavior in the rotenone-induced mice model. Repeated baicalein treatment reduced α-synuclein aggregation, inhibited neuroinflammation, and maintained neurotransmitters homeostasis. 15
Our in vivo study showed that baicalein possesses anti-inflammatory activities by inhibiting α-synuclein aggregation, inflammasome activation and cathepsin B production in the SN. Moreover, baicalein is of therapeutic significance because it inhibits apoptosis and autophagy in the nigrostriatal dopaminergic system of rat brain.2
9. Clinical behavior:
Sodium butyrate (NaB) was administered into PD mice for 6 weeks. NaB significantly reduced the turning and total time in pole test, and increased the average velocity in open field test when compared with PD control mice, indicating the most effective alleviation of PD-induced motor disorder. 16
NaB+T The combination treatment significantly reduced motor deficits as evidenced after rotarod, narrow beam walk, and open field tests. Novel object location and recognition tests were performed to govern cognitive abnormality associated with advanced stage PD, which was overcome by the combination treatment3
Echinacoside (ECH) is the main active ingredient of a widely used Chinese herb cistanche, which has been proven to elicit neuroprotective effects in models of neurodegenerative diseases. In this study, we found that ECH could improve PD-like symptoms in MPTP-lesioned mouse model. We further showed that the underlying mechanism of the action of ECH was associated with enhancing autophagy in neurons via bind to Sirt1 directly and affect FoxO expression. Our study demonstrated ECH as a potential therapeutic agent against PD. 1
Our results demonstrated that paeoniflorin restored the motor performance impairment caused by MPTP, inhibited apoptosis, and protected the ultrastructure of neurons. Paeoniflorin treatment also resulted in the dose-dependent upregulation of an antiapoptotic protein, B-cell lymphoma-2, at the mRNA and protein levels, similar to the effects of the positive control, selegiline. In contrast, paeoniflorin treatment downregulated the expression of pro-apoptotic proteins BCL2-Associated X2, α-synuclein, and PKC-δ at the mRNA and protein levels, as well as the level of the activated form of nuclear factor kappa B (p-NF-κB p65). 18
It was observed that TGPC (peony) treatment (150, 300 mg/kg) significantly reversed MPTP induced PD-like behaviors, such as reduced locomotive activity in the open field test, prolonged time to turn downward on the ball (T-turn) and to climb down the whole pole (T-descend) in the pole test, decreased movement scores in the traction test and extended the latency to fall in the hanging wire test. 21
Baicalein, a flavonoid extracted from the herb Scutellaria baicalensis Georgi, exhibits anti-PD activity through alleviation of its motor symptoms. However, its effects on non-motor symptoms were barely reported. 15
References
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