The Inflammatory Puzzle: Piecing together the Links between Neuroinflammation and Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that has a complex genetic basis. Through advancements in genetic screening, researchers have identified more than 40 mutant genes associated with ALS, some of which impact immune function. Neuroinflammation, with abnormal activation of immune cells and excessive production of inflammatory cytokines in the central nervous system, significantly contributes to the pathophysiology of ALS. In this review, we examine recent evidence on the involvement of ALS-associated mutant genes in immune dysregulation, with a specific focus on the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and N6-methyladenosine (m 6 A)-mediated immune regulation in the context of neurodegeneration. We also discuss the perturbation of immune cell homeostasis in both the central nervous system and peripheral tissues in ALS. Furthermore, we explore the advancements made in the emerging genetic and cell-based therapies for ALS. This review underscores the complex relationship between ALS and neuroinflammation, highlighting the potential to identify modifiable factors for therapeutic intervention. A deeper understanding of the connection between neuroinflammation and the risk of ALS is crucial for advancing effective treatments for this debilitating disorder.

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

“…Recently, immune dysregulation has been suspected [ 171 , 172 , 173 ], with neuroinflammation being invoked in general [ 174 , 175 , 176 ] and for ALS in particular [ 177 , 178 , 179 ], especially concerning activation of microglia and astrocytes [ 180 , 181 ]. It is interesting that microglia communicate with [ 182 ], and can be activated by [ 183 ], mast cells, unique effector immune cells that are ubiquitous in the body and are critical in allergies [ 184 ], but also inflammatory processes [ 185 ].…”

Modulation of NLRP3 inflammasome-related-inflammation via RIPK1/RIPK3-DRP1 or HIF-1α signaling by phenothiazine in hypothermic and normothermic neuroprotection after acute ischemic stroke

“…It accounts for up to 85 % of all types of strokes [ 3 , 4 ]. Inflammatory responses and cell death is the hallmark of stroke pathology [ 5 , 6 ]. Currently, revascularization is the main treatment for ischemic stroke [ 7 ], however patients reached by this therapy often require supplementary neuroprotection strategies [ [8] , [9] , [10] ].…”

Effects of Pathogenic Mutants of the Neuroprotective RNase 5-Angiogenin in Amyotrophic Lateral Sclerosis (ALS)

“…Again, although not being the topic of this review, it must be recalled that neuroinflammation events consequent to protein aggregation are deleterious for cell life span and therefore cause the pathological manifestations of neurodegenerative diseases [ 64 , 65 ], like ALS [ 66 ]. Hence, the block of protein aberrant aggregation might consequently avoid, or reduce, these inflammatory consequences.…”