Immune Signaling Kinases in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disorder of motor neurons in adults, with a median survival of 3–5 years after appearance of symptoms, and with no curative treatment currently available. Frontotemporal dementia (FTD) is also an adult-onset neurodegenerative disease, displaying not only clinical overlap with ALS, but also significant similarities at genetic and pathologic levels. Apart from the progressive loss of neurons and the accumulation of protein inclusions in certain cells and tissues, both disorders are characterized by chronic inflammation mediated by activated microglia and astrocytes, with an early and critical impact of neurodegeneration along the disease course. Despite the progress made in the last two decades in our knowledge around these disorders, the underlying molecular mechanisms of such non-cell autonomous neuronal loss still need to be clarified. In particular, immune signaling kinases are currently thought to have a key role in determining the neuroprotective or neurodegenerative nature of the central and peripheral immune states in health and disease. This review provides a comprehensive and updated view of the proposed mechanisms, therapeutic potential, and ongoing clinical trials of immune-related kinases that have been linked to ALS and/or FTD, by covering the more established TBK1, RIPK1/3, RACK I, and EPHA4 kinases, as well as other emerging players in ALS and FTD immune signaling.

TBK1 inhibitors enhance transfection efficiency by suppressing p62/SQSTM1 phosphorylation

“…However, no significant damage was observed in our experiments using different cell types. This finding is consistent with the fact that TBK1 inhibitors have been applied to clinical trials in humans as drugs to treat amyotrophic lateral sclerosis, diabetes, and cancer (Bailly, 2022; García‐García et al, 2021; Oakes et al, 2017; Runde et al, 2022). The use of TBK1 inhibitors to enhance transfection efficiency is simple yet effective.…”

MAPK/MAK/MRK overlapping kinase (MOK) controls microglial inflammatory/type-I IFN responses via Brd4 and is involved in ALS

“…The broad relevance of our findings is further evidenced by two recent studies revealing associations between MOK gene expression levels in peripheral leukocytes with blood pressure 64 and with type-1 diabetes 65 , which supports a possible role for MOK in immune dysregulation in the context of other pathological scenarios. Indeed, protein kinases, including immune-related kinases, have been shown to play crucial roles in the physiopathology of ALS and other neurodegenerative proteinopathies and have recently emerged as attractive therapeutic targets in various neurodegenerative disorders 66,67 . Therefore, the identification of MOK-regulated proteins and downstream signalling pathways in immune cells, particularly in the context of neuroinflammation, could set the bases for therapeutic targeting of key pathogenic pathways in ALS and other inflammation-related disorders.…”

Research Progress on the Role of Microglia Membrane Proteins or Receptors in Neuroinflammation and Degeneration

“…Microglia-mediated chronic inflammation in the brain is one of the important early pathological features of neurodegenerative diseases (Guo and Zhu, 2021;Teipel et al, 2022). What's more, activation and proliferation of microglia and astrocytes can lead to an increased production of the various inflammatory cytokines (García-García et al, 2021), such as IL-L, IL-6, interleukin-8 (IL-8), TNF-α and inducible nitric oxide synthase (iNOS), which can cause inflammation in the brain (Zhao et al, 2021). Ro5-4864 and PK11195, they are Peripheral benzodiazepine receptors agonist and antagonist, respectively.…”