Abstract
The abnormal mislocalisation and ubiquitinated protein aggregation of the TAR DNA binding protein 43 (TDP-43) within the cytoplasm of neurons and glia in the central nervous system (CNS) is a pathological hallmark of early-onset neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The pathomechanisms underlying abnormal mislocalisation and aggregation of TDP-43 remain unknown. However, there is a growing body of evidence implicating neuroinflammation and immune-mediated mechanisms in the pathogenesis of neurodegeneration. Importantly, most of the evidence for an active role of immunity and inflammation in the pathogenesis of ALS and FTD relates specifically to TDP-43, posing the question as to whether immune-mediated mechanisms could hold the key to understanding TDP-43’s underlying role in neurodegeneration in both diseases. Therefore, this review aims to piece together key lines of evidence for the specific association of TDP-43 with key immune and inflammatory pathways to explore the nature of this relationship and the implications for potential pathomechanisms underlying neurodegeneration in ALS and FTD.
Highlights
A significant line of evidence for the role of immunity and inflammation in the pathogenesis of neurodegeneration underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is that the majority of causative and susceptibility genes associated with TAR DNA binding protein 43 (TDP-43) pathology are highly expressed in innate immune cells and are increasingly implicated in key immune and inflammatory pathways
Both Jun N terminal kinase (JNK) and p38 are identified as immune response kinases responsible for regulating fly immunity and oxidative stress and the innate immune response are identified as key determinants of TDP-43 mediated toxicity in Drosophila motor neurons [141]
This study demonstrated that complement activation and/or its dysregulation could play an important role in motor neuron loss and neuromuscular junction denervation and a heightened complement activation and enhanced C5aR1 signalling could contribute to the pathophysiology of the TDP-43Q331K ALS model
Summary
The innate immune system is the body’s first line of defence against pathogens and plays a central yet varying role in both health and disease. A significant line of evidence for the role of immunity and inflammation in the pathogenesis of neurodegeneration underlying ALS and FTD is that the majority of causative and susceptibility genes associated with TDP-43 pathology are highly expressed in innate immune cells and are increasingly implicated in key immune and inflammatory pathways. These genes include C9orf, GRN, and TBK1, among others (Table 1). TBK1 could potentially represent a direct link between neuroinflammation and kinases in the neurodegeneration underlying ALS and FTD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
