Table 2 Dysregulated expression and potential mechanisms of the 10 hub drug target genes in patients with PD.

AKT1

Dysregulation of the Akt1-CREB pathway was observed in

postmortem brain samples from individuals with PD. Activation of the Akt1-CREB pathway has the potential to prevent neurodegeneration in PD, as Akt1 can inhibit programmed cell death in dopaminergic neurons through a transcriptional mechanism.

Kim⁶²

TNF

The level of TNF-α increased in the post mortem examination of the brain and cerebrospinal fluid of the patients with PD. TNFα binds to the TNFR1 receptor which leads to downstream activation of caspase 8 and caspase 3. Hence TNFR1 can lead to apoptosis of the dopaminergic neuron.

Amin⁶³

SLC6A3

SLC6A3 encodes the dopamine transporter(DAT). DAT mainly

presents on the neuron terminals in SN, and is necessary for dopaminergic neurotransmission to control its intensity and duration

Sossi⁶⁴

MAOA

Monoamine oxidase (MAO) is one of the primary enzymes regulating metabolism of neurotransmitters such as dopamine. MAO-A is mainly responsible for regulating the phasic and tonic DA levels in the striatum by mediating DA degradation.

Cho⁶⁵

IL1B

Increased IL-1β was revealed in both peripheral blood and CSF among patients with PD. Proinflammatory factors IL-1β can induce oxidative stress, neuronal death and in particular the loss of dopaminergic neurons in PD.

Qu⁶⁶

IL6

Increased peripheral blood and CSF level of IL-6 was found in PD patients. The increased IL-6 level in the SN region and plasma are related to PD progression. Chronic exposure to IL-6 during neuronal development can lead to cell damage and death in a subpopulation of developing granule neurons.

Qu⁶⁶

APP

β-amyloid precursor protein (APP) is a membrane-bound protein. The APP intracellular domain promotes LRRK2 expression and activates LRRK2-mediated neurotoxicity via FOXO3a.

Zhang⁶⁷

MAOB

MAOB expression is significantly increased in the reactive astrocytes of the substantia nigra pars compacta (SNpc) in PD. Pharmacological blockade of MAOB inhibitors has been well documented to prevent MPTP-induced PD pathology and parkinsonian motor symptoms.

Moriguchi⁶⁸

SRC

C-SRC is a ubiquitously expressed non-receptor tyrosine kinase.

C-SRC promotes the release and uptake of α‐syn and that c‐src inhibition attenuates α‐syn cell‐to‐cell transmission

Choi⁶⁹

DRD2

DRD2 encodes the D2 subtype of the dopamine receptor.

The mechanisms underlying DRD2-mediated immune response in PD may involve nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, renin-angiotensin system, and αB-crystallin.

Xia⁷⁰