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Perspective  |  Open Access  |  27 Jun 2023

Can alpha-synuclein be both the cause and a consequence of Parkinson's disease?

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Ageing Neur Dis 2023;3:10.
10.20517/and.2023.05 |  © The Author(s) 2023.
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Alpha-synuclein (α-syn) is a presynaptic and nuclear protein that has been inextricably linked to Parkinson’s disease (PD). It regulates the presynaptic activities of neurons, but its aggregation and spreading have been associated with a group of diseases termed synucleinopathies. Here, we examined the commonly held view that α-syn caused disease and explored the concept that α-syn aggregation may be a consequence of pathobiology. Future therapies may need to encompass α-syn both a cause and consequence of the disease process.


Alpha-synuclein, Parkinson’s disease, Lewy bodies, iron


Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting approximately 7 million to 9 million people around the world[1], and the incidence of PD is growing even faster than that of Alzheimer’s disease (AD)[1,2]. The Global Burden of Disease Study has estimated that there will be 12.9 million people suffering from PD by 2040[1], indicating increasing health expenses to individuals and societies.

PD is classically characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Within this region, there are Lewy bodies (LBs) and Lewy neurites (LNs) that are partially made from misfolded alpha-synuclein (α-syn), as well as elevated iron[3]. In addition to the SNpc, the pathogenesis of PD also affects a broad range of organs, including the gut, heart, eyes, and several other nuclei in the brain[4,5].

α-Syn is estimated to be 8.5% of the total protein content of the LBs[6]. Over the last few decades, α-syn is generally believed to contribute to the pathogenesis of PD, where excessive production of α-syn or its abnormal structure leads to aberrant aggregation that mediates disruption of cellular homeostasis[7]. Following the results from clinical and translational investigations studying α-syn, we here present an argument that α-syn can be both the cause and a consequence of PD. For example, genetic changes in the α-syn gene (SNCA) are sufficient to induce PD, which supports that α-syn is the cause of the disease. On the other hand, α-syn aggregation found in human PD may result from dysregulations of the brain biochemicals, and therefore it can be considered a consequence of the disease. This fact is essential since the evolution of new therapies may require an approach that encompasses both possibilities.


α-Syn, which was first isolated from neural tissue in Pacific electric ray in 1988, is localized to the presynaptic nerve terminal[8]. In 1997, Polymeropoulos et al. discovered the first specific gene mutation associated with familial PD (A53T)[9-11]. The link between SNCA (which encodes α-syn protein) and PD has led to the development of antibodies against α-syn, which were applied to pathological sections of tissue from patients with PD[7].

α-Syn is a small protein composed of 143 amino acids and is about 15 kDa in size[12]. The N-terminal region (residues 1-60) of α-syn is mainly composed of seven highly conserved duplicated 11 residues (KTKEGV), with most of the known α-syn mutation sites[13,14]. The central nonamyloid component (NAC) region (residues 61-95) is composed of non-polar side chains, which are hydrophobic and tend to form β-sheet structures, resulting in its tendency to aggregate and toxicity[15,16]. The non-conserved C-terminal domain (residues 96-140) is negatively charged, and many phosphorylation sites are in this region, such as S129, Y125, Y133, and Y136[17], which are putatively thought to be critical for its aggregation and neurotoxicity [Figure 1]. In particular, phosphorylation of S129 was identified as the main posttranslational modification of α-syn in familial and sporadic Lewy body disease[18].

Can alpha-synuclein be both the cause and a consequence of Parkinson's disease?

Figure 1. Schematic structure of α-synuclein. The arrows indicate disease-related mutations (red) and phosphorylation sites (blue). NAC: Nonamyloid component.

α-Syn is predominantly localized at presynaptic terminals, where it associates with synaptic vesicles[14]. The presynaptic location of synuclein and its interaction with membranes strongly indicate a role in endocytosis and exocytosis. In synuclein knockout mice, the action potentials were reduced, the synaptic structure was changed, and age-dependent neuronal dysfunction was observed[19]. A recent study found that the α-syn mutation (A53T and E46K) further accelerated the endocytosis of vesicles[20], collectively supporting a crucial role of α-syn in neuronal endocytosis.

Overexpression of α-syn in dopaminergic neurons of substantia nigra (SN) results in impaired neurotransmission, suggesting α-syn may play an attenuating role in neurotransmitter release[21,22]. Synapsins, members of the cytoplasmic regulatory family of synaptic vesicles (SV), promote the interaction between α-syn and synaptic vesicles[23]. α-syn can be inserted into the synapsin/SV liquid phase to facilitate SV clustering[23]. Additionally, the neurotransmitter release from presynaptic nerve terminals requires a cycle of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-complex assembly and disassembly, where α-syn is directly bound to the SNARE-complex (v-SNARE and t-SNARE) and promotes its assembly[24,25]. α-Syn oligomers may sequester the v-SNARE using multiple binding sites for t-SNARE on vesicles and inhibit SNARE-mediated vesicle fusion[26]. Moreover, α/β/γ-synuclein triple knockout mice exhibited an age-dependent decrease in SNARE-complex assembly, leading to neurological impairments[25].


The genetic evidence from the SNCA gene

Both rare point mutations and copy number gains of SNCA genes have been reported to lead to autosomal dominant PD. The frequency of SNCA mutations in sporadic and familial PD is approximately 0.2% and 1%-2%, respectively[27]. These point mutations of SNCA include A53T, A30P, E46K, A53E, H50Q, G51D, A18T, and A29S[13,28], and SNCA may be duplicated or triplicated [Table 1].

Table 1

Major genetic causes associated with Parkinsonism and synuclein pathology

GeneMutationPrevalence in PD populationAlpha syn pathologyReferences
SNCAA53T1.39%-4.5%Cortical and subcortical LB distribution is different from iPD. Some with LBs in the hypothalamus and amygdala. Neuronal loss and gliosis exist in the amygdala. [43,140-146]
LRRK2G2019S0.54%-5.1%SN and LC neurons degeneration and LBs formation. 64.7% of people with LB. LB pathology in SN and LC. Some with LB in the amygdala, prefrontal, and motor cortices.[117-119,142,147-149]
PINK1-1.14%-6.9%Loss of neurons in SNpc. Two case studies show the absence of Lewy pathology, while another study showed a family with LB and aberrant neurites in the reticular nuclei, SNpc, and Meynert nucleus, but none in LC.[150-156]
PRKN-4.55%-17%Neuronal degeneration, LB pathology in 16.7%-37.5% people. No Lewy pathology in the hippocampus or cerebral cortex. Some without LB in the SNpc. SNpc neuronal loss is as severe as in iPD.[119,129,154,157,158]
GBA-7%-15%Widespread and abundant α-syn pathology in all GBA mutation carriers, increased frequency of diffuse neocortical Lewy body-type pathology.[159-163]

These carriers of the A53T (age of onset 35-59 years old) mutation have an approximately 10-year earlier onset than the other mutations [e.g., A30P (54-76 years old), E46K (50-69 years old), and H50Q (54-70 years old)[29]]. Both A53T and A30P mutations accelerate the aggregation of α-syn[30]. Mouse models that overexpress the human α-syn A53T exhibit progressive neurodegeneration in the SN, and age-dependent motor and non-motor symptoms of PD[31]. The H50Q mutation has been reported to strongly stabilize α-syn fibrils and significantly accelerate their aggregation and amyloid formation[32]. The age of onset, clinical features, and progression of the patients with G51D mutation are most similar to the SNCA triplication and A53T mutations[33]. They are frequently associated with early-onset PD as well as cognitive impairment and hallucinations[33]. A53E (40-60 years old) mutation was found to attenuate α-syn aggregation and amyloid formation[34]; however, it increases the cellular toxicity induced by MPP+[32]. The A18T (50 years old) and A29S (60 years old) mutations were first found in sporadic PD[35], and they promote α-syn fibrillation and cytotoxicity[35,36]. There was also a P117T variant reported in thirteen subjects without symptoms of PD[28].

Multiplications of the SNCA gene have been reported to cause PD as well. SNCA duplication results in clinical phenotypes similar to idiopathic PD[37], including a relatively late onset of age and slowly progressed neurodegeneration, which was first identified in a French family[38]. Interestingly, SNCA duplication may not consistently cause parkinsonism, as cognitive impairment has been observed in carriers without parkinsonism[39]. This seems to be a common phenomenon in neurodegenerative diseases, as the duplication of MAPT, the gene encoding tau protein, also causes neurodegeneration[40-42]. In contrast, SNCA triplication resulted in a much earlier onset of the disease and rapid progression, as has been reported in several races[43-45]. Collectively, it suggests that the copy number of SNCA may increase the disease severity, supporting the notion that α-syn may be the cause of PD.

α-Syn injection models of PD

Besides genetic evidence, recently utilized α-syn injection models also support the notion that a single protein may cause the disease. In 2012, Luk et al. reported that intra-striatal inoculation of mouse α-syn preformed fibrils (PFF) in WT mice induced LBs/LNs pathology, dopaminergic neuron loss, and motor deficits[46]. Such results have been robustly repeated, and several studies have injected α-syn PFFs into different brain regions to investigate its spreading in the brain[47-49].

Olfactory bulbs (OB) are thought to be the first places where α-syn pathology appears[50,51]. Injection of α-syn PFFs into the OB of WT mice resulted in the spreading of α-syn pathology trans-neuronally to over 40 other brain regions, including the amygdala, entorhinal cortex, locus coeruleus (LC), and SNpc[52]. However, these mice presented no alteration of locomotion or anxiety level with deficits in odor discrimination[53].

The SN is the most severely damaged brain region in PD, and indeed injection of α-syn PFFs directly into the SN promoted α-syn accumulation in the SNpc and striatum, activated microglia in the SN, reduced dopaminergic neuron number, and caused striatal degeneration[54]. The brain homogenates of mice with LB pathology were also injected into the cortex and striatum of WT mice, and α-syn deposition was found across the brain[55].

Systemic administration of α-syn also triggers selective neuronal pathology as seen in PD[56]. Inoculation of α-syn preformed fibrils in the duodenum results in intestinal nervous system dysfunction, increased midbrain dopaminergic neuronal death, and brain stem α-syn pathology, with motor impairment[57]. When injected into the tail vein, the mice exhibited gastrointestinal and olfactory dysfunction, with neuronal degeneration in the midbrain and brain stem[56], mimicking the sequence of pathological events that occurred in PD. In addition, oral or intraperitoneal administration of α-syn can induce α-syn pathology in the brain[58], where intranasally inoculation additionally triggers iron accumulation in microglia but not dopaminergic neuronal loss nor behavioral dysfunction[59].


How α-syn aggregates and spreads in PD

How does Lewy pathology spread in the brain of humans with PD? Braak et al. proposed that misfolded α-syn spreads from a few cells to multiple brain regions over years or decades[60]. They divided PD pathology into six stages[60]. At stages 1 and 2, Lewy pathology is only within the medulla oblongata. In the early symptomatic stage (3 and 4), α-syn inclusions occur in SN, the anteromedial temporal mesocortex, and the brain stem. At stages 5 and 6, Lewy pathology in the area previously described becomes more severe; the pathology continues to spread to the adjoining high-order sensory association areas of the neocortex. However, it is important to note that only about half of the human studies show a distribution of Lewy pathology in the brain consistent with the Braak staging model[61]. A more recent imaging study raised the hypotheses of an alternative model of transmission of α-syn in PD[62], including brain-first and body-first symptoms. The pathology of the body-first (from bottom to top) subtype originated from the intestinal or surrounding autonomous nervous system, then rose to the brain through the vagus nerve. The pathology of the brain-first (from top to bottom) subtype is initially present in the brain itself, presenting as REM sleep behavior disorder (RBD) and then descending to other tissues (heart, gut).

Either working model of α-syn spreading in human PD initiated from α-syn aggregates is more likely triggered by other factors, unlike the materials injected into the mice brains. In vitro studies have confirmed that these aggregates, either oligomers or fibrils, are neurotoxic[63,64]. Therefore, it is necessary to study the inducement of α-syn oligomer formation and fibrosis. These factors include dopamine[65], lipids[66], metal[67], and others.

Dopamine (DA) and its analogs or metabolites can regulate α-syn aggregation[68,69], and in PD, dopamine reduction in the SNpc as a consequence of SN neuronal loss directly causes motor disability[70]. Hence, the supplementation of DA medications temporally restores motor functions and increases the lifespan of PD patients[71,72]. It has been found that, at least in models of PD, the enrichment of dopamine with iron distinguished SN from nearby regions, such as the ventral tegmental area (VTA), as the valuable brain region for parkinsonism[73]. Such enrichment also provides a highly active chemical environment for α-syn aggregation. Importantly it has been reported that α-syn forms SDS-resistant soluble oligomers in the presence of dopamine[74], which in turn depolymerizes fibrils[75]. The mechanism was investigated, and it is suggested that the oxidation of dopamine resulted in the accumulation of dopamine quinone in the cytoplasm, which interacts with α-syn to inhibit the conversion of oligomers into fibrils[75]. In addition, α-syn also plays a role in regulating dopamine biosynthesis[76]. A loss of soluble α-syn, by reduced expression or promoted aggregation, increases dopamine synthesis with an accompanying increase in reactive dopamine metabolites[76].

An elevation of iron in the SNpc was first observed in the brains of PD patients in 1924[77], which subsequently was confirmed by several studies[3,78-82]. Interestingly, the increase of iron differs across cell types in PD. Dopaminergic neurons in the SN of PD patients exhibit a twofold increase in cellular iron levels[83,84], whereas the iron content of astrocytes remains unchanged. Microglia show an accumulation of about 25%, while Olig2-stained oligodendroglia exhibit an increase of nearly 150%[84]. Since nigral iron accumulation in PD is correlated with disease motor severity and dopaminergic neurodegeneration[85,86], it is hypothesized that iron participates in PD pathogenesis[87] and the mechanism of its accumulation has been linked with tau-APP (Amyloid Precursor Protein) dysfunction in PD[82,88-91]. Biochemically, iron directly binds to α-syn and promotes α-syn aggregation in a dose-dependent manner[67,87,92-94]. An iron reactive element (IRE) has been found in the RNA of α-syn[95-97]. Iron regulatory proteins (IRP) can bind to the IRE of α-syn mRNA and inhibits the translation of α-syn transcripts. However, iron can bind to IRP, leading to the separation of IRP and IRE, thereby promoting α-syn expression and aggregation[98,99]. Indirectly, iron also promotes aggregation or oligomer formation of α-syn by regulating the phosphorylation of α-syn[100]. In both human and animal models of PD, preclinical studies using iron-modulating agents have been tested to reduce α-syn aggregation and toxicity[93,101-103]. PBT434, a novel quinazolinone compound, binds to iron, significantly reduces iron-mediated α-syn aggregation, rescues the loss of SN dopaminergic neurons, and ameliorates motor dysfunction in PD mouse models[93]. Interestingly, a recent study found that brain iron enrichment attenuated α-syn diffusion in a dose-dependent manner after α-syn PFF injection in mice[104]. In addition to iron, copper and zinc also interact with α-syn[105,106]. In PD cases, copper is dysregulated[105]. Copper binding to α-syn with a higher affinity at the residues 48-53 induces aggregation of α-syn[107]. Copper binding leads to the exposure of highly amyloidogenic NAC region of α-syn, which increases fibril formation[107]. Zinc ions have been reported to directly interact with α-syn and promote its aggregation[106], where it displayed the modulation effects on the secondary structures of the α-syn NAC region[108].

In PD, LBs have been reported to contain membrane fragments, vesicles, and organelles including mitochondria and lysosomes, suggesting that disruption of neuronal membrane homeostasis may occur in PD and may participate in α-syn aggregation[66]. α-syn aggregation may be triggered by the destruction of its affinity for the membrane. The lipid/α-syn ratio was suggested as one important factor for determining α-syn aggregation under quiescent conditions[109]. Under physiological conditions, the lipid/α-syn ratio is high, and limited monomeric α-syn is present freely in cells since excess lipid maintains α-syn to bind to the membrane surface in a helical conformation. The reduction of the lipid/α-syn ratio during PD reduced the binding between α-syn and the cell membrane and α-syn was released available for aggregation. Only a fraction of vesicle-bound α-syn was able to serve as an active nucleation seed to initiate aggregation[110]; however, the release of α-syn to cytosol greatly promotes the nucleation process on the lipid surface, hence promoting the aggregation. On the other hand, the promoted aggregation leads to lowered lipid/α-syn ratios[110], making it a vicious cycle.

Furthermore, growing epidemiological evidence links PD risk to immune disorders and certain infections[111]. Recent research has suggested that the upregulation of α-syn levels is a typical response to infections[112,113]. Especially under specific circumstances, such as genetic predisposition and dysregulated inflammatory response due to aging, monomer α-syn may aggregate into oligomers[114]. These oligomers are then transported by nerve endings and can accumulate in the central nervous system, form pathogenic fibrils, and trigger neurodegeneration[114,115].

Other genes are associated with α-syn pathology

Additionally, it is unlikely that the aggregation process of α-syn initiated spontaneously, and several genes have been identified to cause PD, including leucine-rich repeat kinase 2 (LRRK2), Parkin gene (PRKN), PTEN-induced putative kinase 1 (PINK1), and Glucocerebrosidase (GBA) [Table 1]. Most of which present with α-syn pathology, especially LRRK2 and PRKN. In these cases, the genetic mutations of individual genes other than SNCA are primarily responsible for parkinsonism and synuclein deposition, as seen in idiopathic PD.

LRRK2 is a serine/threonine kinase[116], and clinical results showed that SN and LC neurons were lost in PD patients with G2019S mutation, and 64.7% of patients were accompanied by LB pathology in SN and LC[117-119] and similar motor phenotype and progression as in idiopathic Parkinson’s disease (iPD)[120]. In mice, the mutation caused enhanced α-syn aggregation and propagation, with significant loss of SN dopaminergic neurons accompanied by motor dysfunction[121]. In rodents, inhibitors of LRRK2 kinase activity reduce α-syn pathology, which may be related to activating the autophagic lysosomal pathway[122,123]. A recent study found that LRRK2 also promotes a neuroinflammatory cascade by phosphorylation and inducing nuclear translocation of NFATc2, blocking α-syn clearance in microglia of mice; in addition, NFATc2 expression levels and immune reactivity were increased in PD patients[124].

Parkin, encoded by the PRKN gene, was identified in 1998 from a patient who exhibited an early onset of parkinsonism but with slower progression[125] and less cognitive impairment than in iPD[126]. It is the most common factor (10%-20%) for early onset PD across ethnic groups, which typically develops in carriers before age 41 to 50[119]. It is an E3 ubiquitin ligase protein composed of a Ubl domain, a large unstructured loop, and four zinc-binding domains[127]. The main pathological feature of Parkin PD is the loss of SN neurons, but only 16.7%-37.5% of patients with LB pathology in SN and LC[128,129]. Overexpression of parkin was reported to prevent neurodegeneration induced by α-syn in rats expressing human A30P α-synuclein[130], and elevated oxidative stress seen in PD affects parkin ligase activity by altering its posttranslational modification[131]. It is hypothesized that parkin may be essential for LB formation even though the mutation carriers don’t typically exhibit LB pathology.


It is a commonly held view that α-syn has a central role in the pathogenesis of PD and other α-synucleinopathies. We reviewed the evidence and concluded that α-syn can be both a cause and a pathological consequence of the disease in different conditions. On the one hand, genetic changes in the SNCA are sufficient to induce PD, as well as α-syn aggregation injections into the animals, which support that α-syn can cause the disease, or at least the symptoms of PD. On the other hand, α-syn aggregation found in human PD may result from dysregulation of the brain chemicals such as dopamine or iron, and therefore it can be considered a consequence of the disease [Figure 2]. In addition, mutations of several other genes also result in parkinsonism and α-syn deposition, further supporting the notion that α-syn is not the only cause of the disease.

Can alpha-synuclein be both the cause and a consequence of Parkinson's disease?

Figure 2. α-Synuclein can be both the cause and a consequence of Parkinson’s disease.

Incidental Lewy body disease (iLBD) describes people with LBs or LNs but without clinical symptoms of parkinsonism or dementia. Clinical studies showed that the distribution of LBs in iLBD was similar to that in PD[132]. Compared with the normal control group, the neuron density of locus coeruleus (LC) was significantly reduced, and the TH immunoreactivity in the striatum and the epicardial sympathetic fiber was decreased[133], but this reduction was not as severe as that in the PD group. These suggested that incidental Lewy body disease may be pre-symptomatic PD. Importantly, both studies in humans and monkeys have shown an age-related accumulation of α-syn aggregation and LBs decades before any disease[134]. These suggest that there may be some threshold effect when normal age-related nigral cell loss is accelerated or a “tipping point” of α-syn increase and clinical disease. However, when the disease reaches a critical point, iLBD exhibits symptoms of PD. Here nor can LB be treated only as a symptom, shown as an example of the complex role of α-syn in disease.

The multiple roles of α-syn in PD are similar to other misfolded proteins in neurodegenerative diseases. For example, genetic mutations in the amyloid precursor protein (APP) cause Alzheimer’s disease (AD)[135], and direct injection of Aβ oligomers into the hippocampus of wild-type mice also causes cognitive impairment and hippocampal neuron loss[136]. On the other hand, A typical symptom of AD is the deposition of amyloid beta (Aβ)[137], modified by several factors. In this case, Aβ is also both cause and consequence of AD. Currently, therapies targeting antibodies against Aβ have been approved for clinical use[138], with limited understanding of their mechanisms and characteristics. And these anti-Aβ antibodies can cause other side effects[138,139]. For example, anti-Aβ therapy can damage long-term brain health by accelerating brain atrophy[139]. Therefore, we still have doubts about Aβ therapies. Removing plaque may not result in the expected improvements, since the factors promoting plaque formation were not limited. This is an essential question as the evolution of new therapies may require an approach that encompasses both possibilities.

Currently, α-syn targeted therapy in synucleinopathies is mainly aimed at eliminating α-syn aggregation. Understanding that α-syn can be both the cause and a consequence of disease under different circumstances is critical for future mechanistic studies and drug discoveries.


Authors’ contributions

Conceived the review: Finkelstein DI, Lei P

Wrote and edited the manuscript: Chen K, Lei P, Finkelstein DI

Critically revised the work: Guo YJ

Availability of data and materials

Not applicable.

Financial support and sponsorship

This work was supported by grants from the National Natural Science Foundation of China (82071191, 32000724) and the West China Hospital 1.3.5 project for disciplines of excellence (ZYYC20009).

Conflict of interest

Both Finkelstein DI and Lei P served as editorial members of Ageing and Neurodegenerative Diseases, and Lei P is the Guest Editor of this Special Issue “Ferroptosis in Neurological Disorders”. Neither Finkelstein DI nor Lei P was involved in the editorial process of the work.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.


© The Author(s) 2023.


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Chen K, Guo YJ, Lei P, Finkelstein DI. Can alpha-synuclein be both the cause and a consequence of Parkinson's disease?. Ageing Neur Dis 2023;3:10.

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Chen K, Guo YJ, Lei P, Finkelstein DI. Can alpha-synuclein be both the cause and a consequence of Parkinson's disease?. Ageing and Neurodegenerative Diseases. 2023; 3(2): 10.

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Kang Chen, Yu-Jie Guo, Peng Lei, David I Finkelstein. 2023. "Can alpha-synuclein be both the cause and a consequence of Parkinson's disease?" Ageing and Neurodegenerative Diseases. 3, no.2: 10.

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Chen, K.; Guo Y.J.; Lei P.; Finkelstein DI. Can alpha-synuclein be both the cause and a consequence of Parkinson's disease?. Ageing. Neur. Dis. 2023, 3, 10.

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