Targeting New Candidate Genes by Small Molecules Approaching Neurodegenerative Diseases

Abstract

Neurodegenerative diseases (NDs) are among the most feared of the disorders that afflict humankind for the lack of specific diagnostic tests and effective treatments. Understanding the molecular, cellular, biochemical changes of NDs may hold therapeutic promise against debilitating central nerve system (CNS) disorders. In the present review, we summarized the clinical presentations and biology backgrounds of NDs, including Parkinson's disease (PD), Huntington's disease (HD), and Alzheimer's disease (AD) and explored the role of molecular mechanisms, including dys-regulation of epigenetic control mechanisms, Ataxia-telangiectasia-mutated protein kinase (ATM), and neuroinflammation in the pathogenesis of NDs. Targeting these mechanisms may hold therapeutic promise against these devastating diseases.

Keywords: Alzheimer’s disease (AD); Ataxia-telangiectasia-mutated protein kinase (ATM); Huntington’s disease (HD); Parkinson’s disease (PD); epigenetics; neurodegenerative diseases (NDs); neuroinflammation.

Figure 1

Illustration of epigenetic mechanisms. The process of DNA condensation and relaxation is controlled principally through histone post-translational modifications, such as methylation, acetylation, phosphorylation, ubiquitination, sumoylation, etc. Histone acetyltransferases (HATs), mono- and poly-ubiquitination, and ubiquitin-specific proteases (USPs) may cause uncoiling chromatin (euchromatin) and allow transcriptional factor access to the DNA (right); whereas DNA methyltransferases (DNMTs), histone deacetylases (HDACs), mono- and poly-ubiquitination (Ub), ubiquitin-specific proteases (USPs), Polycomb repressive complex 1(PRC1)/Polycomb repressive complex 2 (PRC2), and Small ubiquitin-related modifier (SUMO) modification may result in coiling chromatin (heterochromatin) and prevent transcription factor access to DNA, leading to transcriptional repression. TF: transcription factor.

Figure 2

Molecular cascades of DNA damages initiating repair systems and cell cycle progression. In response to DNA damage, including single-strand beaks (SSBs) and double-stranded breaks (DSB), the Ataxia-telangiectasia-mutated protein kinase (ATM)/ Ataxia-telangiectasia and Rad3 related protein (ATR) signaling pathways are activated, leading to the phosphorylation and activation of CHK1 and CHK2 and to the subsequent phosphorylation of CDC25. Phosphorylated CDC25 inhibits activation of cyclin B/CDK1, resulting in G2 arrest. Activated ATM/ATR pathways also activate p53-dependent signaling to arrest G2 through the activation of P21, which inhibits cyclin B/CDK1 complexes. Lines with arrow heads indicate activation, while lines with bar heads indicate inhibition.

Figure 3

Schematic representation of the tryptophan (TRP) metabolic pathway. Most TRP is used as the precursor of kynurenine (KYN) pathway, in which TRP is firstly oxidized by TRP 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO) to the kynurenine (KYN). There are at least three pathways for KYN metabolism. (1) KYN aminotransferase (KAT) pathway: KYN is catabolized by KAT to form KYN acid (KYNA), which antagonizes N-methyl-D-aspartate receptors (NMDAR) and α7 nicotinic receptors (α7nAChR); (2) kynurenine 3-monoxygenase (KMO) pathway: KYN is converted into 3-HK by KMO. 3-HK is converted into 3-HAA by KAT; (3) KYNase pathway: KYN is metabolized by KYNase to form anthranilic acid (AA), which is converted into 3-hydroxyanthranilic acid (3-HAA) by AA3MO. 3-HAA is oxidized by 3-hydroxyanthranilic acid oxidase (HAAO) to quinolinic acid (QUIN), which generates NAD⁺ through quinolinate phosphoribosyltransferase (QPRT). Additionally, TRP is metabolized to 5-hydroxytryptophan (5-HTP) through TRP hydroxylase (TPH) and tetrahydrobiopterin (BH4). Serotonin is synthesized from 5-HTP via aromatic acid decarboxylase (AADC) and the vitamin B6. Serotonin is converted into 5-Hydroxyindoleacetic acid (5-HIAA) or 5-hydroxytryptophol (5-HTOL) by monoamine oxidase (MAO) or into N-acetylserotinin by N-acetyl-transferase (NAT). Melatonin is generated via the hydroxyl-indole O methyltransferase (HOMT).