CN-121975933-A - Application of cGAS as target in Leigh syndrome prevention/treatment

Abstract

The invention discloses an application of cGAS as a target in the prevention/treatment of Leigh syndrome. According to the invention, ndufs4 is constructed, and a cGAS DKO gene knockout mouse model is researched, so that the result shows that the cGAS can be knocked out to improve the gliosis phenomenon of the mice with the Lishi syndrome and reduce the gliosis phenomenon, and the neuroinflammation is inhibited. The invention provides a new potential drug target and a treatment strategy for treating the Lishi syndrome, and lays a foundation for developing new drugs for treating the Lishi syndrome.

Inventors

• GONG RUI
• ZHANG BOXIN
• YANG QIANXI
• LI HONGDA

Assignees

• 重庆医科大学

Dates

Publication Date

20260505

Application Date

20260115

Claims (7)

1. Use of cgas as a target in screening for a medicament for the prevention of Leigh syndrome.
2. Use of cgas as a target in screening for a drug for the treatment of Leigh syndrome.
3. 3. The method according to claim 1 or 2, wherein the cGAS is cyclic GMP-AMP synthetase or a gene encoding the same.
4. 4. The method according to claim 1 or 2, wherein the agent inhibits cGAS expression.
5. 5. The use according to claim 1 or 2, wherein the medicament improves gliosis in patients with Lishi syndrome.
6. 6. The method according to claim 1 or 2, wherein the agent inhibits abnormal activation of the cGAS-STING pathway.
7. 7. The method according to claim 1 or 2, wherein the drug inhibits neuroinflammation.

Description

Application of cGAS as target in Leigh syndrome prevention/treatment Technical Field The invention belongs to the technical field of biological medicines, and relates to an application of cGAS as a target in Leigh syndrome prevention/treatment. Background Leigh Syndrome (LS), also known as subacute necrotic or Leigh encephalopathy, is a hereditary mitochondrial disease that occurs during infancy and is a fatal neurodegenerative disease caused by mitochondrial dysfunction, and its typical pathological features include abnormal energy metabolism, progressive neuronal death, abnormally elevated levels of Reactive Oxygen Species (ROS), and concomitant mutation of mitochondrial DNA (mtDNA). In recent years, it has been discovered that mitochondrial damage may activate intracellular innate immune pathways (e.g., cGAS-STING signaling axes) through abnormal release of mtDNA, thereby driving inflammatory phenotypic transformation of microglia and astrocytes, creating a pro-inflammatory microenvironment and exacerbating neurodegenerative disease. However, in Leigh's syndrome, it is not clear whether mitochondrial dysfunction or oxidative stress directly leads to cytoplasmic leakage of mtDNA, and the specific mechanism how such leakage events are involved in disease progression through the neuroinflammatory pathway. With respect to the study of LS pathology, it has been reported that significant increases in Iba1+ cells, which are characteristic of activated microglia cells, have been found in various areas of the brain of Leigh's syndrome patients and are associated with neuronal loss. The pre-clinical model commonly used at present for Leigh's syndrome is Ndufs4 mutant mice, ndufs gene encodes a subunit of mitochondrial complex I, whose role in the human body is mainly related to the energy metabolism of the cell, as it is involved in the process of mitochondrial Electron Transport Chain (ETC), which is critical for the production of the energy molecule Adenosine Triphosphate (ATP) by the cell. The Ndufs mutated iPS-brain organoids show activated inflammatory pathways, and partial ablation of microglial cells in a Leigh syndrome mouse model improves the survival rate of the mice, and simultaneously improves the neurological deficit. Reactive Oxygen Species (ROS) and neuronal mitochondrial dysfunction are widely recognized as key factors in neurodegenerative diseases, and studies have shown that ROS and neuronal mitochondrial dysfunction lead to accumulation of Lipid Droplets (LD) in glial cells. In the Drosophila model, ROS activate c-Jun-N terminal kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP), which results in triggering accumulation of LD in glial cells, which occurs in the early or initial stages of neurodegeneration, and lipid peroxidation of accumulated lipids occurs under the action of ROS. By targeting lipase overexpression or reducing ROS levels, reducing LD accumulation and lipid peroxidation in glial cells has been demonstrated to significantly delay the onset of neurodegenerative disease. In the Ndufs gene mutated mouse model, a phenomenon of colloidal LD accumulation similar to drosophila was observed, indicating that LD accumulation after mitochondrial dysfunction is an evolutionarily conserved phenomenon, possibly as a temporary marker and facilitator in the early stages of neurodegenerative diseases. Primary mitochondrial dysfunction is the root cause of Leigh syndrome, where related genes are mainly expressed in neuronal cells, where the affected central nervous system is critical, which can lead to motor and respiratory dysfunction, seizures and premature death. However, only specific neuronal populations are affected. There are studies reporting that inactivation of Ndufs4 in glutamatergic neurons expressing Vglut2 leads to reduced neuronal firing, brain stem inflammation, motor and respiratory dysfunction, and the passage of time. In contrast, deletion of Ndufs4 in gabaergic neurons causes basal ganglion inflammation, but without involvement of movement or respiration, but is accompanied by hypothermia and severe seizures before death. LS is currently not treated, but administration of rapamycin to Ndufs mutant mice has been reported to delay onset of neurological symptoms, reduce neuroinflammation and prevent brain injury, and Protein Kinase C (PKC) down-regulation has been determined to be a key factor in rapamycin-treated Ndufs mutant mice, and the use of PKC inhibitors can increase survival of Ndufs mutant mice, delay neurological damage and reduce inflammation. Acarbose, a drug that prolongs the longevity of mice and delays normal aging, also inhibits disease symptoms and improves survival of Ndufs4 -/- mice. Unlike rapamycin, acarbose can restore disease phenotype independently of inhibition of rapamycin mechanism targets. In addition, the co-administration of rapamycin and acarbose further increases the survival rate of Ndufs4 -/- mice and delays disease phenotype. Whi