Mushroom Natural Products in Neurodegenerative Disease Drug Discovery

Abstract

The variety of drugs available to treat neurodegenerative diseases is limited. Most of these drug's efficacy is restricted by individual genetics and disease stages and usually do not prevent neurodegeneration acting long after irreversible damage has already occurred. Thus, drugs targeting the molecular mechanisms underlying subsequent neurodegeneration have the potential to negate symptom manifestation and subsequent neurodegeneration. Neuroinflammation is a common feature of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, and is associated with the activation of the NLRP3 inflammasome, which in turn leads to neurodegeneration. Inflammasome activation and oligomerisation is suggested to be a major driver of disease progression occurring in microglia. With several natural products and natural product derivatives currently in clinical trials, mushrooms have been highlighted as a rich and largely untapped source of biologically active compounds in both in vitro and in vivo neurodegenerative disease models, partially supported by successful clinical trial evaluations. Additionally, novel high-throughput methods for the screening of natural product compound libraries are being developed to help accelerate the neurodegenerative disease drug discovery process, targeting neuroinflammation. However, the breadth of research relating to mushroom natural product high-throughput screening is limited, providing an exciting opportunity for further detailed investigations.

Keywords: Alzheimer’s disease (AD); Huntington’s disease (HD); Parkinson’s disease (PD); amyloid-β (Aβ); multiple sclerosis (MS); natural products (NPs); neurodegenerative diseases (NDs); nucleotide-binding oligomerisation domain- leucine-rich repeat- and pyrin domain-containing 3 (NLRP3); polyglutamine (poly Q); synuclein α (SNCA).

Figure 1

A schematic representation of the model proposed for microglial activation [15]. Microglia undergo a transition from M2 “resting” state to M1 “active” state which is induced by various molecular signals. Figure created with BioRender.com (accessed on 1 November 2022).

Figure 2

The molecular mechanisms underlying the activation of the NLRP3 inflammasome complex in AD and PD. Abnormal protein aggregates such as Aβ can selectively bind TLR4, SNCA can selectively bind TLR2 and scavenger receptor CD36, or both can be phagocytosed [67]. Phagocytosed Aβ and SNCA drive the production of cathepsins which increase K⁺ efflux, TNF-α and NO production, and NLRP3 oligomerisation [67,68]. Intracellular messengers such as MYD88, TRIF, and Fyn act to upregulate NF-κB which stimulates the production of proinflammatory cytokine pro-IL-1β, pro-IL-18, the production of NLRP3, and additionally increases the expression of caspase-11 and IFN-β [63,64,67,69,70,71]. The ER drives Ca²⁺ uptake in mitochondria, along with intracellular ion efflux and promotes mROS production, which in turn drives NLRP3 oligomerisation, also via the release of ptdLNS4P [4,20]. The activation of the inflammasome complex allows pro-caspase-1 to self-cleave forming active caspase-1 which can then induce the maturation of pro-IL-1β and pro-IL-18, cleave GSDMD initiating pyroptosis, drive the invasion of immune cells via increasing the expression of adhesion molecules, sensitise neutrophils to chemo-attractants, and stimulate vasodilation [67,69,70]. Figure created with BioRender.com (accessed on 1 November 2022).

Figure 3

Molecular structures of erinacine A and C (33 & 34), 7-methoxydesoxo-narchinol (30), kanshone N (31), narchinal A (32), and ganoresinoid A (49), all of which possess anti-neuroinflammatory processes [119,120,121,124].