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.

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

“…Autophagy-and UPS-dependent degradation of unfolded and misfolded proteins is important to prevent their accumulation, aggregation, and spreading [11,49,[53][54][55][56][57][58]74]. Upon ubiquitination, most misfolded proteins are degraded by the proteasome 26S (P26S), which is formed by a catalytic core (P20S) and two regulatory subunits (P19S, also known as PA700) capping the ends of P20S [11,75].…”

“…To date, plenty of evidence exists linking alterations of either autophagy or UPS with the aggregation, spreading and toxicity of so called prionoids, including α-syn, Aβ, tau, huntingtin, SOD1, TDP-43 and FUS [19,29,[52][53][54][55][56][57][58][59][60]. Albeit being both autophagy and UPS implicated in the clearance of the above-mentioned proteins, recent biochemical and morphological studies have added to this scenario, focusing on the cross-talk between these two systems [61][62][63][64][65][66][67][68][69][70][71][72][73].…”

The Multi-Faceted Effect of Curcumin in Glioblastoma from Rescuing Cell Clearance to Autophagy-Independent Effects

“…This natural compound has been used for centuries in the traditional Indian Ayurvedic and Chinese medicine for treating respiratory and liver disorders, infections, allergies, and rheumatisms [ 3 ]. Nowadays, curcumin is widely used due to its multiple biological activities, encompassing anti-inflammatory, anti-oxidant, scavenging reactive oxidative species (ROS), regulation of mitochondrial homeostasis, stem cell modulation, and neurogenesis [ 4 ]. Hence, curcumin may be useful in a wide range of human diseases, encompassing cardiovascular [ 5 , 6 ], inflammatory [ 7 , 8 ], and metabolic disorders [ 9 , 10 , 11 ].…”

“…In particular, in the last decades, phytochemicals, and especially curcumin, have gathered increasing interest in both experimental and pre-clinical studies for their beneficial effects on the central nervous system (CNS). Among dietary polyphenolic compounds, curcumin appears as a useful agent for adjunct therapy in a variety of neurogenerative disorders (NDDs) [ 4 , 12 ]. In fact, curcumin appears to exert multiple neuroprotective effects through its strong anti-oxidant, anti-inflammatory, and anti-protein aggregation properties [ 13 ].…”

Potential Antidepressant Effects of Scutellaria baicalensis, Hericium erinaceus and Rhodiola rosea

“…In fact, these herbal compounds may also act through yet unexplored biological pathways that are implicated in both mood and neurological disorders. For instance, some recent studies indicate that a variety of herbal compounds, including S. baicalensis and R. rosea, may produce neuroprotective effects by modulating autophagy, which is key to maintain intracellular homeostasis under oxidative stress conditions by degrading abnormal proteins or organelles, especially mitochondria [174][175][176][177]. For instance, baicalin-induced autophagy is associated with inhibition of the mitochondrial apoptotic pathway and protection against experimental traumatic brain injury [178], while saliroside-induced autophagy counteracts alpha-synuclein aggregation and toxicity [179].…”