Brain alarm by self-extracellular nucleic acids: from neuroinflammation to neurodegeneration

Abstract

Neurological disorders such as stroke, multiple sclerosis, as well as the neurodegenerative diseases Parkinson's or Alzheimer's disease are accompanied or even powered by danger associated molecular patterns (DAMPs), defined as endogenous molecules released from stressed or damaged tissue. Besides protein-related DAMPs or “alarmins”, numerous nucleic acid DAMPs exist in body fluids, such as cell-free nuclear and mitochondrial DNA as well as different species of extracellular RNA, collectively termed as self-extracellular nucleic acids (SENAs). Among these, microRNA, long non-coding RNAs, circular RNAs and extracellular ribosomal RNA constitute the majority of RNA-based DAMPs. Upon tissue injury, necrosis or apoptosis, such SENAs are released from neuronal, immune and other cells predominantly in association with extracellular vesicles and may be translocated to target cells where they can induce intracellular regulatory pathways in gene transcription and translation. The majority of SENA-induced signaling reactions in the brain appear to be related to neuroinflammatory processes, often causally associated with the onset or progression of the respective disease. In this review, the impact of the diverse types of SENAs on neuroinflammatory and neurodegenerative diseases will be discussed. Based on the accumulating knowledge in this field, several specific antagonistic approaches are presented that could serve as therapeutic interventions to lower the pathological outcome of the indicated brain disorders.

CAP2 contributes to Parkinson’s disease diagnosed by neutrophil extracellular trap-related immune activity

“…Besides, dopamine-induced extracellular traps (ETs) are functional ( 46 ). There are two main functional regions of NETs present: the generation of oversized NETs scaffolds (consisting of whole decompressed nucDNA, histones, and various antimicrobial proteins and enzymes) used to trap and kill microorganisms in the initial immune response when neutrophils are stimulated; and the other, where activated platelets also act as an inducer of NETosis by providing adhesive interactions with neutrophils, which ultimately results in the immediate formation of cellular aggregates, from which the NETs are released to stimulate prothrombotic functions ( 22 ). Meanwhile, not only neutrophils but also mast cells, eosinophils, basophils, macrophages and also microglial cells as the resident immune cell of the CNS have been described to release nucDNA-containing ETs in response to various stimuli ( 47 , 48 ).…”

“…Different types of exDNA such cfDNA or NETs have been identified under various pathophysiological conditions (including hyperinflammation, tumor progression or neurodegeneration) in the brain and can contribute to disease onset and progression in various ways ( 19 – 21 ). A common denominator in the pathogenesis is the release of mtDNA and cfDNA, the latter being particularly available in NETs, whereby both parameters may serve as disease biomarker ( 22 ). At present, studies in neurodegenerative diseases, such as multiple spinal sclerosis ( 23 ) and Alzheimer’s disease ( 24 ) have been investigated in relation to NETs, as well as PD has been reported to demonstrate a link between mtDNA-induced inflammation and PD ( 25 ), while the mechanism of the association with NETs is still unknown.…”

Monoclonal Antibody Therapy in Alzheimer’s Disease

“…They possess phagocytic capabilities that enable them to clear harmful substances from the environment and trigger tissue inflammation [ 50 , 51 , 52 ]. Inflammation is originally a defensive reaction, yet its prolonged state can be harmful to the tissue [ 52 , 53 , 54 ]. Consequently, brain inflammation becomes a distinctive feature of Alzheimer’s disease [ 54 ].…”

“…Inflammation is originally a defensive reaction, yet its prolonged state can be harmful to the tissue [ 52 , 53 , 54 ]. Consequently, brain inflammation becomes a distinctive feature of Alzheimer’s disease [ 54 ]. As early events in AD’s pathophysiology unfold, including the increase in Aβ levels even before the formation of senile plaques, microglial activation has been observed [ 55 ].…”

Editorial: Noncoding RNA-based spatiotemporal modulation and therapeutics in neuroinflammation

“…Neuroinflammation is a multifactorial process occurring in the central nervous system (CNS) that is intimately linked to temporal and spatial regulation of gene expression mediated by noncoding RNAs (ncRNAs). ncRNAs are present at high concentrations in the CNS and show specific multidimensional expression, exerting immunomodulatory effects via direct or indirect interactions with various effector proteins or other molecules to form complex networks that regulate downstream immune response pathways ( 1 , 2 ). Next-generation sequencing has identified various ncRNAs dysregulated in CNS disorders, including long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) ( 3 – 5 ).…”