The potential of natural products to inhibit abnormal aggregation of α-Synuclein in the treatment of Parkinson's disease

Abstract

Parkinson's disease (PD), as a refractory neurological disorder with complex etiology, currently lacks effective therapeutic agents. Natural products (NPs), derived from plants, animals, or microbes, have shown promising effects in PD models through their antioxidative and anti-inflammatory properties, as well as the enhancement of mitochondrial homeostasis and autophagy. The misfolding and deposition of α-Synuclein (α-Syn), due to abnormal overproduction and impaired clearance, being central to the death of dopamine (DA) neurons. Thus, inhibiting α-Syn misfolding and aggregation has become a critical focus in PD discovery. This review highlights NPs that can reduce α-Syn aggregation by preventing its overproduction and misfolding, emphasizing their potential as novel drugs or adjunctive therapies for PD treatment, thereby providing further insights for clinical translation.

Keywords: Parkinson’s disease; aggregation; misfolding; natural products; α-Synuclein.

FIGURE 1

Structure and Function of α-Syn Domains. The structural of α-Syn is illustrated, emphasizing the N-terminal region (residues 1–60), the NAC region (residues 61–95), and the C-terminal region (residues 96–140). Arrows indicate the sites of familial Parkinson’s disease mutations. The distinct functions of the N-terminal, NAC region, and C-terminal domains are delineated, highlighting their respective roles in the protein’s overall activity and pathology.

FIGURE 2

(A) Under pathological conditions, naturally disordered α-Syn monomers abnormally aggregate to form oligomers (primary nucleation). These oligomers subsequently extend to generate protofibrils and mature fibrils (secondary nucleation). (B) Various types of NPs can inhibit the conversion of α-Syn monomers into oligomers, thereby suppressing oligomer fibrillation and preventing fibril formation. Furthermore, NPs facilitate the degradation of fibrillar products.

FIGURE 3

(A) The underlying mechanism of α-Syn-induced mitochondrial dysfunction leads to increased intracellular ROS. (1) α-Syn disrupts the activity of mitochondrial electron transport chain complexes, including complex I (Luth et al., 2014), III (Ellis et al., 2005), IV (Danyu et al., 2019; Elkon et al., 2002) and V (Ludtmann et al., 2018), with the most pronounced damage observed in complex I. (2) The accumulation of α-Syn affects the stability of the endoplasmic reticulum-mitochondria association, leading to impaired Ca²⁺ transport and subsequent the disruption of mitochondrial calcium homeostasis (Cali et al., 2012; Paillusson et al., 2017). (3) Fibrillated products of α-Syn interact with components of the mitochondrial permeability transition pore, such as the voltage-dependent anion channel (VDAC), adenine nucleotide translocator (ANT), and mitochondrial matrix protein cyclophilin D (CypD), This interaction activates the mitochondrial permeability transition pore and altering mitochondrial permeability (Torpey et al., 2020; Halestrap, 2009; Lu et al., 2013; Zhu et al., 2011). (4) Cardiolipin (CL)-rich environments enhance the interaction between α-Syn and mitochondria, increasing mitochondrial membrane permeability (Ghio et al., 2019). (5) α-Syn interacts with Parkin and PINK1, disrupting the mitochondrial quality control (MQC) pathway (Thorne and Tumbarello, 2022). (7) α-Syn binds to the TOM and TIM proteins on the outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM), interfering with the mitochondrial protein import mechanism (Thorne and Tumbarello, 2022). (B) Pathological α-Syn activates microglia and astrocytes, leading to sustained neuroinflammation and neurotoxicity. (1) Pathological α-Syn enhances the activation of p38/ATF2, TLR, and NF-κB in microglia, and promoting their transition to the M1 phenotype. (2) α-Syn enters and activates astrocytes through endocytosis and exocytosis (Lee et al., 2010). Activated astrocytes produce cytokines, chemokines, and toxic factors, which further enhance microglial activation. M1-type microglia release tumor necrosis factor-alpha (TNF-α), interleukin-1α (IL-1α), and complement component 1q (C1q), promoting the formation of A1-type astrocytes. (C) Overexpression and abnormal aggregation of α-Syn in the gastrointestinal tract can lead to its transport to the brain via the gut-brain axis, resulting in accumulation within the CNS. α-Syn is predominantly deposited in several brain regions, with the SN and striatum being the most commonly affected areas.

FIGURE 4

Chemical structure of polyphenolic compounds.

FIGURE 5

Chemical structure of flavonoid-like compounds.

FIGURE 6

Chemical structure of Naphthoquinones.

FIGURE 7

Chemical structure of other natural products.

FIGURE 8

Chemical structure of quinoline and indole alkaloids.

FIGURE 9

Chemical structure of nicotine, caffeine, squalamine and trodusquemine.