Phytochemicals Bridging Autophagy Induction and Alpha-Synuclein Degradation in Parkinsonism

Abstract

Among nutraceuticals, phytochemical-rich compounds represent a source of naturally-derived bioactive principles, which are extensively studied for potential beneficial effects in a variety of disorders ranging from cardiovascular and metabolic diseases to cancer and neurodegeneration. In the brain, phytochemicals produce a number of biological effects such as modulation of neurotransmitter activity, growth factor induction, antioxidant and anti-inflammatory activity, stem cell modulation/neurogenesis, regulation of mitochondrial homeostasis, and counteracting protein aggregation through modulation of protein-folding chaperones and the cell clearing systems autophagy and proteasome. In particular, the ability of phytochemicals in restoring proteostasis through autophagy induction took center stage in recent research on neurodegenerative disorders such as Parkinson's disease (PD). Indeed, autophagy dysfunctions and α-syn aggregation represent two interdependent downstream biochemical events, which concur in the parkinsonian brain, and which are targeted by phytochemicals administration. Therefore, in the present review we discuss evidence about the autophagy-based neuroprotective effects of specific phytochemical-rich plants in experimental parkinsonism, with a special focus on their ability to counteract alpha-synuclein aggregation and toxicity. Although further studies are needed to confirm the autophagy-based effects of some phytochemicals in parkinsonism, the evidence discussed here suggests that rescuing autophagy through natural compounds may play a role in preserving dopamine (DA) neuron integrity by counteracting the aggregation, toxicity, and prion-like spreading of α-syn, which remains a hallmark of PD.

Keywords: ashwagandha; bacosides; catechins; cell-clearing pathways; curcumin; gallic/asiatic acids; metabolic syndrome; resveratrol; synucleinopathy.

Figure 1

The effects of phytochemical-rich plants in counteracting the cascade (plain black arrows) of molecular events, which occur in synucleinopathies and Parkinson’s disease (PD). These include (i) oxidative stress and accumulation of Reactive Oxygen Species (ROS) arising from altered dopamine (DA) metabolism (DA oxidation), (ii) endoplasmic reticulum (ER) and mitochondrial stress, (iii) structural alterations of α-syn, formation of insoluble aggregates up to Lewy bodies where native α-syn monomers are sequestered (dashed black arrows), (iv) neuroinflammation, and (v) autophagy impairment due to either altered autophagosome biogenesis or impaired fusion between lysosomes and autophagosomes (dashed black arrows). The buildup of ubiquitinated α-syn aggregates contributes to further impairing the autophagy machinery thus fueling a vicious circle where damaged autophagy substrates accumulate due to impaired clearance and turnover. This, in turn, contributes to increasing the overall vulnerability of DA neurons and promoting the spreading of α-syn (dashed black arrows). Phytochemicals from the plants represented here confer neuroprotection by preventing or reverting (blue arrows) this pathological cascade, starting from autophagy induction to inhibition of α-syn aggregation, neuroinflammation, and oxidative stress.

Figure 2

A schematic overview of the beneficial effects of phytochemical-rich plants in α-syn aggregation dynamics (light grey circles), and related molecular mechanisms (central dark grey circle) occurring in PD. In a physiological state, a dynamic equilibrium (blue arrows) exists between α-syn natively unfolded monomers and membrane-bound α-helical monomers (secondary structure). Environmental toxins or mutations/multiplications within α-syn gene (SNCA) favor α-syn misfolding/overexpression and drive a pathological cascade of conversion up to insoluble fibrils and Lewy body formation. This is associated with a generalized impairment of cell homeostasis consisting of altered DA metabolism and synaptic dysfunction, oxidative stress, mitochondrial damage, autophagy impairment, and cell-to-cell spreading of misfolded and aggregated α-syn conformers. Phytochemicals found within Curcuma longa, Bacopa monnieri, Centella asiatica, Camellia sinensis, Withania somnifera and Vitis vinifera are able to reverse/prevent the pathological conversion cascade of α-syn while counteracting alterations of DA neurotransmission, oxidative stress, mitochondrial damage and autophagy impairment (green shade).

Figure 3

Autophagy-related molecular pathways which are targeted by phytochemical-rich plants. Phytochemicals induce autophagy by acting at several molecular levels. Curcumin (C. longa), catechins of green tea (C. sinensis), resveratrol (V. vinifera) and bacosides (B. monnieri) act as mTOR inhibitors, which leads to autophagy induction either through activation of ULK1/Atg13 or transcription factor EB (TFEB). In particular, curcumin, green tea catechins, and C. asiatica activate TFEB to promote its translocation to the nucleus, and the subsequent induction of autophagy-related genes. Catechins of green tea and withanolides from W. somnifera may also activate autophagy through inhibition of Glycogen Synthase Kinase 3 Beta (GSK-3β), while resveratrol fosters the activation of the autophagy-promoting transcription factor FoxO3. Again, green tea catechins, resveratrol and B. monnieri activate autophagy through enhancement of AMP-activated Protein Kinase (AMPK), which in turn is an upstream inhibitor of mTOR and an activator of Sirtuin-1 (SIRT1). Activation of SIRT1-dependent autophagy through deacetylation of Atg proteins is mainly induced by resveratrol and C. asiatica. Again, W. somnifera may also act upstream of autophagy by modulating the IGF1-Akt axis, although a role has not been confirmed yet. Plain black arrows indicate pathways which act as upstream inhibitors of autophagy while plain orange arrows indicate pathways which promote autophagy. Dashed black arrows indicate pathways converging towards autophagy machinery. Red dashed boxes indicate the specific phytochemicals which activate autophagy by acting as inhibitors (red line) or inducers (red cross) of specific autophagy-related molecules.