The role of inflammation in neurodegeneration—new insights and advances

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are adult-onset progressive neurodegenerative diseases that belong to the same disease spectrum. In ALS, the motor system is predominantly affected by degeneration of motor neurons (MNs) in the motor cortex, brainstem, and spinal cord, whereas in FTLD, the frontal and anterior temporal cortexes are predominantly affected.

Neuroinflammation is present during the neurodegenerative process. This inflammatory response to neuronal damage is regarded to be significant and may play a role in disease pathogenesis.

"The role of inflammation in neurodegeneration: novel insights into the role of the immune system in C9orf72 HRE-mediated ALS/FTD" was published in Mol Neurodegener on March 18, 2022 by Philip Van Damme's group at KU Leuven's Department of Neuroscience, Experimental Neurology, and Leuven Brain Institute (LBI), reviewing the mechanisms of ALS development mediated by C9orf72-HRE, with a particular focus on the role played by neuroinflammation in the disease process.

Three non-reciprocal hypotheses explain the role of C9orf72 HRE in disease.

1. A loss-of-function mechanism in which reduced levels of C9orf72 transcripts lead to reduced levels of C9orf72 protein, more widely known as C9orf72 haploinsufficiency.

1. Toxic gain-of-function mechanisms formed by RNA foci, where righteous and antisense HRE RNAs segregate RNA-binding proteins and other proteins.
2. Toxic gain-of-function mechanism resulting in toxic DPR via RAN translation of both sense and antisense HRE RNAs.

Activated intracellular signaling pathways in glial cells in neuroinflammation.

1. Janus kinase signal transducer and activator of transcription (JAK-STAT).
2. Nuclear factor kappa light chain enhancer of activated B cells (NF-?B) and mitogen-activated protein kinase (MAPK).
3. The NOD-like receptor family pyrin domain-containing 3 (NLRP3).

Although the exact role of neuroinflammation in neurodegeneration remains controversial, dysregulation of the immune system is a pathological hallmark of almost all neurodegenerative diseases. It consists of increased activation of glial cells and activation of pro-inflammatory MAPK and NF-?B signaling pathways, increased cell surface expression of cell adhesion molecules, increased cytoplasmic expression of pro-inflammatory enzymes, and increased release of pro-inflammatory secretory proteins such as cytokines, chemokines, and growth factors.

While neuroinflammation has been studied primarily in patients and in vivo models because of the inherent nature of the process requiring multiple cell types and secreted molecular interactions, recent advances in the field of iPSC have also made it possible to study a number of dysregulated processes in related cell types in vitro. In addition, iPSCs can help study the cell-autonomous mechanisms of the deregulation process, as cells are homogeneous with respect to their interactions with other cell types.

Recently, a new key player in the immunology field has been associated with ALS and C9-ALS/FTD, which is termed the cyclic GMP-AMP synthase (cGAS)-interferon gene stimulator (STING) pathway. In addition to being an important component of the innate immune system, STING signaling is also involved in autophagy, apoptosis, and necroptosis.

The STING signaling pathway is primarily regulated by autophagic degradation of STING proteins. Because C9orf72 protein is involved in endolysosomal transport and autophagy, a decrease in C9orf72 levels causes STING protein degradation to be delayed and the type I interferon response to be activated. Furthermore, pharmacological inhibition of this pathway with STING antagonists was able to reduce the overactive type I interferon response, highlighting the STING pathway as a potential therapeutic target.

The C9orf72 gene is highly expressed in innate immune cells, and several studies have shown immune system dysfunction caused by C9orf72 gene mutations. More research is needed to elucidate the role of neuroinflammation in the initiation and propagation of the neurodegenerative process in C9-ALS/FTD, as well as the crosstalk among the peripheral and central nervous systems, as well as the immune system.

Given C9orf72's role in the immune system, anti-inflammatory therapy in C9-ALS/FTD is promising, and better characterization of the neuroinflammatory response will hopefully lead to more targeted therapeutic strategies.

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