Role of neuroinflammation and latent transcription factors in pathogenesis of Parkinson's disease.
Parkinson's disease (PD) the second most common age-associated progressive neurodegenerative disorder is characterized by loss of dopaminergic neurons, cytoplasmic inclusions of aggregated proteins (Lewy bodies), and neuroinflammation. The inflammation of neurons causes release of various inflammatory mediators (IFNs, EGF, IL5, IL6, HGF, LIF and BMP2). The hallmarks of neuroinflammation are the presence of activated microglia and reactive astrocytes in the parenchyma of the CNS and increased production of cytokines, chemokines, prostaglandins, complement cascade proteins, and reactive oxygen and nitrogen species (ROS/RNS) which in some cases can result in disruption of the blood brain barrier and direct participation of the adaptive immune system. Latent transcription factors such as NF-κB, STAT 3, AP1, and SMAD 7, Toll like receptors and FAF 1 are constitutively upregulated in activated microglia. Toll-like receptors when activated promote NF-κB signaling thus promoting a vicious cycle of neuroinflammation. These transcription factors take dopaminergic neurons to apoptotic pathway via p53 and other death domain receptors. Neuroprotective signaling pathways such as mTOR, SOCS, and TGF-β down regulated during development of PD. YY1 signaling, which has protective effect against α-Synuclein toxicity, is significantly decreased in PD patients. In summary we can say that transcription factors promoting inflammation such as NF-κB, STAT 3, AP 1, and Toll-like receptors are constitutively upregulated in PD, while neuroprotective pathways such as mTOR, TGF-β, and YY1 are substantially downregulated in microglia of PD patients.
a Department of Pharmacology & Therapeutics , King George's Medical University , Lucknow , India.
Rishi
R
Pal
a Department of Pharmacology & Therapeutics , King George's Medical University , Lucknow , India.
Prafulla Chandra
PC
Tiwari
a Department of Pharmacology & Therapeutics , King George's Medical University , Lucknow , India.
Rajendra
R
Nath
a Department of Pharmacology & Therapeutics , King George's Medical University , Lucknow , India.
Kamlesh Kumar
KK
Pant
D017209:Apoptosis / Q000502:physiology; D016207:Cytokines / Q000378:metabolism*; D004660:Encephalitis / Q000209:etiology*; D006801:Humans; D010300:Parkinson Disease / Q000150:complications* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*
D016207:Cytokines; D014157:Transcription Factors
Apoptosis; Neuro-degenerative disorder; Neuroinflammation; Signaling pathways; Transcription factor