DNA Leakage-Induced Neurodegeneration
Parkinson's disease is one of the neurodegenerative diseases characterized
by motor and various non-motor symptoms, with many aspects of its pathogenesis
still remaining unclear. It has been suggested that mitochondrial and lysosomal
dysfunctions are involved in the pathology of Parkinson's disease, although
the detailed mechanisms were not well understood. We have reported numerous
studies on the pathology and novel models of Parkinson's disease (refer
to our publications). Here, we describe the latest findings.
In our 2021 study published in Nature Communications, we reported that
mitochondrial DNA leakage into the cytoplasm induces cytotoxicity and neurodegeneration
in cell cultures and zebrafish models of Parkinson's disease. In cultured
cells, the reduction of Parkinson’s disease-related gene products PINK1,
GBA, or ATP13A2 led to an increase in cytoplasmic mitochondrial DNA, which
induced type I interferon response and cell death. These phenotypes were
ameliorated by overexpression of DNase II, a lysosomal DNA-degrading enzyme,
or by reduction of IFI16, a sensor for mitochondrial DNA. In the gba mutant
zebrafish model of Parkinson’s disease, overexpression of human DNase II
improved motor dysfunction and degeneration of dopaminergic neurons. The
event of mitochondrial DNA leakage into the cytoplasm and its sensor IFI16
accumulation were observed in the lesioned areas of postmortem brains of
Parkinson's disease patients. Our lab's ability to utilize well-preserved
diseased brains for research is one of our unique strengths.
These results suggest that the leakage of mitochondrial DNA into the cytoplasm
could be a significant cause of neurodegeneration in Parkinson's disease.
Targeting the degradation of cytoplasmic mitochondrial DNA or inhibiting
its sensors may lead to potential treatments for Parkinson's disease (Matsui et al., Nat. Commun., 2021, Press release: https://www.bri.niigata-u.ac.jp/research/result/210521.research_findings.pdf）。
Currently, we are delving deeper into the pathology of Parkinson’s disease, while also aiming to unravel the mysteries of other neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, and multiple system atrophy from new perspectives.