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Global Translational Medicine Parkinson’s: From cause to cure

inflammasome is also implicated in PD pathogenesis cGAS-STING-YY1 axis promotes astrocyte aging by
and progression, with the TLR4/TAK1/IRF7 pathway upregulating the expression of LCN2, thereby facilitating
regulating NLRP3 expression and activity, influencing the progression of PD. 16
dopaminergic neuronal apoptosis. 12 In summary, various inflammatory pathways, including
Emerging studies highlight the cyclic guanosine NF-κB, TLR signaling, and the cGAS-STING pathway, are
monophosphate-adenosine monophosphate synthase– closely interconnected and contribute to the occurrence
Stimulator of Interferon Genes (cGAS-STING) signaling and progression of PD.
pathway as an essential component of the innate immune
system involved in PD. The cGAS-STING signaling 2.3. α-Synuclein aggregation
pathway regulates numerous cellular processes, such as α-Synuclein is the main component of Lewy bodies, a
autophagy, protein synthesis, glycolipid metabolism, DNA pathological hallmark of neuronal degeneration in PD. The
damage repair, cellular senescence, and various forms of abnormal aggregation and propagation of α-syn are closely
cell death. 13 related to the onset and progression of PD. Enriched
at pre-synaptic sites, α-syn associates with vesicles and
PRKN and PINK1, two genes associated with early-
onset PD, play essential roles in mitophagy, the clearance membranes. In its pathological form, it exerts detrimental
effects at the synapse during early disease stages, disrupting
of damaged mitochondria. Research shows that exhaustive vesicle clustering and altering the post-synaptic response to
exercise in Prkn- and Pink1-KO (Prkn and Pink1 ) mice neurotransmitters, ultimately impairing synaptic plasticity.
-/-
-/-
induces a pronounced inflammatory phenotype. With
aging, Prkn ; mutator mice accumulate mitochondrial A recent finding in PD research highlights the self-
-/-
DNA mutations, leading to an inflammatory response. restrictive oligomerization of α-syn on membranes. This
Interestingly, the absence of STING mitigates this process may be associated with the pathological functions
17
inflammatory response and rescues dopaminergic of α-syn, affecting its roles both pre- and post-synaptically.
neuronal loss and motor deficits in aged Prkn ; mutator Breakthroughs in imaging techniques have significantly
-/-
mice. 14 improved the visualization of α-syn pathology in animal
models and PD patients. Researchers have developed a
Withaferin A, a naturally occurring compound with small molecule ligand, C05-05, for in vivo visualization
neuroprotective effects, has shown potential in PD of α-syn deposits in the brain. Using optical and positron
treatment. Whole-genome deep sequencing has linked emission tomography (PET) imaging techniques,
withaferin A’s neuroprotective effects to the DJ1-NRF2- C05-05 enables the tracking of fibril formation along
STING pathway in the SNpc. Studies using transgenic neural pathways and the subsequent destruction of these
mice (Dj1-KO, Nrf2-KO, STINGgt/gt, and STING-KO) structures. In vitro experiments have demonstrated the
and immunostaining techniques have confirmed the high-affinity binding of 18F-C05-05 to α-syn aggregates in
significant role of STING in PD pathogenesis. 15 human brain tissue. Notably, compared to healthy controls,

Mechanistically, the cGAS-STING pathway is activated an enhanced PET-detectable 18F-C05-05 signal has been
in response to pathogen invasion, mitochondrial damage, observed in the midbrain of PD and dementia with Lewy
or genomic instability, which leads to the accumulation bodies patients, marking the first in vivo visualization of
of cytoplasmic double-stranded (ds) DNA. The DNA α-syn pathology in these diseases. 18
receptor cGAS recognizes this dsDNA and catalyzes the α-Syn not only accumulates intracellularly but also
formation of the secondary messenger 2’3’-cGAMP from spreads to other cells through intercellular interactions.
GTP and ATP. cGAMP subsequently binds to the receptor This spread extends from the brain to the gut and
protein STING homodimer located on the endoplasmic other peripheral tissues through the vagus nerve. Such
reticulum membrane, initiating a conformational transcellular and trans-tissue propagation increases α-syn
change that activates STING. The synthesis of cGAMP is accumulation across multiple brain regions, exacerbating
considered the critical first step in activating the cGAS- PD symptoms. Furthermore, α-syn interacts with tau
STING pathway. protein, co-localizing within Lewy bodies and affecting

In mammals, the catalytic activity of cGAS is triggered α-syn pathology in PD.
by its interaction with dsDNA, a process that has been Researchers have developed gut PD mouse models
extensively studied and is now well understood through expressing α-syn N103 or tau N368 with a red fluorescent
structural and biochemical research. It has been found protein in the enteric nervous system, but not in the
13
that PD is associated with aging and the senescence of brain. These models simulate the spread of α-syn and
astrocytes. Further investigations have revealed that the tau co-pathology from the gut to the brain, accompanied

Volume 3 Issue 4 (2024) 3 doi: 10.36922/gtm.5082