DNA Leakage-Induced Neurodegeneration
Alzheimer’s disease is one of the most common neurodegenerative disorders,
characterized by memory impairment and cognitive decline. The accumulation
of amyloid-β is widely recognized as a pathological hallmark of the disease.
However, many aspects of the mechanisms underlying Alzheimer’s disease
remain unclear. Amyloid precursor protein (APP), the precursor of amyloid-β,
has long been a major focus of Alzheimer’s disease research, but the physiological
functions of APP itself within neurons have not been fully understood.
In a study published in PNAS in 2026, we used cultured cells, human iPSC-derived
neurons, mouse brains, and postmortem brains from patients with Alzheimer’s
disease to show that APP helps maintain cellular homeostasis by promoting
the extracellular clearance of nuclear-derived waste generated upon nuclear
damage through a mechanism called lysosomal exocytosis. In cultured cells,
reduction of APP led to the intracellular accumulation of nuclear-derived
waste, accompanied by increased inflammatory responses and cell death.
In contrast, expression of wild-type APP ameliorated these abnormalities.
Furthermore, APP variants associated with familial Alzheimer’s disease
were found to be insufficient in this nuclear-derived waste clearance function.
In mouse brains, reducing APP under conditions of DNA damage exacerbated
DNA damage, cell death, and abnormalities in nuclear morphology, whereas
expression of wild-type APP alleviated these pathological changes. By contrast,
mutant APP did not show this protective effect. These findings suggest
that APP is not merely a molecule that gives rise to amyloid-β, but may
also function as a protective factor that safeguards neurons against nuclear
stress.
In postmortem brains from patients with Alzheimer’s disease, we observed
abnormalities in neuronal nuclear morphology, accumulation of nuclear-derived
waste in the cytoplasm, increased DNA damage, and reduced levels of APP
per neuron. One of the strengths of our laboratory is access to exceptionally
well-curated human disease brain specimens, which enabled us to examine
whether the mechanisms identified in cellular and animal models may also
be involved in the human disease brain.
Together, these findings suggest that impaired clearance of nuclear-derived
waste may contribute to the pathogenesis of neurodegenerative diseases,
including Alzheimer’s disease. Understanding the mechanisms by which cells
properly eliminate accumulated nuclear-derived waste, and controlling the
inflammation and cell death that arise when this system fails, may provide
new insights into the pathogenesis and therapeutic development of neurodegenerative
diseases, including Alzheimer’s disease (Dougnon et al., PNAS, 2026; https://www.bri.niigata-u.ac.jp/research/result/002448.html).
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.