ReviewRevisiting the role of the innate immune complement system in ALS
Introduction
Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND), and the third most prevalent adult-onset neurodegenerative disease (Renton et al., 2011). The pathogenesis of ALS involves the progressive and selective loss of upper cortical and lower α-motor neurons in the motor cortex, brainstem and spinal cord, as well as denervation of skeletal muscle, leading to symptoms of muscle weakness, fasciculation and ultimately paralysis (Bruijn and Cleveland, 1996; Lee et al., 2013; Zarei et al., 2015). ALS is rapidly fatal, with a median life expectancy of 2–4 years from diagnosis, most commonly as a result of loss of respiratory muscle function. The aetiology of ALS is poorly understood, and the number of ALS cases are predicted to increase in coming years largely due to an ageing population, particularly in developing nations, reaching an estimated 375, 000 cases worldwide by 2040 (Arthur et al., 2016). There are only a few drugs, including Riluzole and Edaravone, that are approved to treat the disease, and these have limited efficacy in patients (Dharmadasa and Kiernan, 2018; Hardiman and van den Berg, 2017). Thus, there is an urgent need to develop new therapeutics that will significantly extend survival and decrease morbidity in ALS.
There are two forms of ALS - familial and sporadic, which make up approximately 10% and 90% of cases respectively. The two aetiologies are phenotypically indistinguishable from each other based on their clinical and pathological features, both resulting in progressive muscle weakness, atrophy and spasticity (Siddique and Siddique, 2008). For familial ALS, a few of the key genes implicated include mutations in C9orf72, SOD1, TARDBP, FUS and VCP (DeJesus-Hernandez et al., 2011; Koppers et al., 2012; Kwiatkowski Jr. et al., 2009; Renton et al., 2011; Rosen et al., 1993; Sreedharan et al., 2008). Asides from genetic predisposition, several theories have been put forward regarding the causes of motor neuron death and muscle denervation in ALS. These include glutamate excitotoxicity, impaired protein homeostasis, aberrant RNA metabolism, mitochondrial abnormalities, axonal defects, impaired DNA repair, dysregulated vesicle transport, radical-mediated oxidative stress and glial and immune dysfunction leading to neuroinflammation (Brown and Al-Chalabi, 2017; Hardiman et al., 2017; Zarei et al., 2015). This review will survey evidence for a role for the innate immune complement system in driving neuroinflammation and contributing to disease progression in ALS. Specifically, it will cover findings regarding the pathways involved, particularly the role of the terminal complement pathway. It will also examine potential future directions for research into the role of the complement system in ALS.
Section snippets
The immune system in neurodegenerative diseases
The immune system has evolved as the body's primary defence against foreign and potentially infectious agents (Hwang and McKenzie, 2013). In vertebrates, we observe two distinct, yet interlinked effector arms that comprise the host's overall immunity. The first of these is the innate immune response, an evolutionarily ancient process that acts through rapid and non-specific targeting of foreign antigens by monocytes, macrophages, dendritic cells and granulocytes (Akira et al., 2006). The second
Complement system activation in the CNS
The complement system is a key component of the innate immune system. It is comprised of a large collection of well over 50 identified blood-circulating and membrane-bound proteins, including receptors and regulators, which act in a cascade manner to augment the immune response and rid the body of exogenous threats in the form of foreign pathogens and noxious self-derived molecules generated by cellular stress responses and death (Kolev et al., 2014). The complement system undertakes its
The terminal complement pathway
The cleavage of C5 leads to the formation of the two major effectors of complement via its two active fragments C5a and C5b. C5a, like C3a, is a small polypeptide, which is considered to be one of the most potent inflammatory molecules generated from the immune response, and exhibits a broad range of biological and pathological functions (Manthey et al., 2009). C5a exerts its effects through two high affinity receptors, the classical and generally predominant signalling receptor C5aR1, and the
Clinical and experimental evidence of upstream complement pathway involvement in ALS
Substantial research has been accumulated from ALS patients investigating levels of complement components during disease progression. Additionally, ALS animal models have been useful in corroborating findings from human patients, as well as allowing investigators to perform disease-modifying interventions in a controlled research environment. Components of various complement activation pathways have been found to be altered in serum samples, neurological tissues and skeletal muscles from ALS
Clinical and experimental evidence of terminal complement involvement in ALS
Somewhat surprisingly, in contrast to the above studies implicating an important role for classical and central complement component in the pathogenesis of ALS, prior studies using knockout mice have indicated no major role for these pathways in disease pathology. Genetic deletion of upstream complement components C1q, C3 and C4 in SOD1 transgenic ALS mouse models showed a reduction in macrophage levels, but ultimately did not show any significant beneficial effects on disease progression and
Future directions towards therapeutic application of complement-targeted drugs in ALS
Current therapies for ALS are inadequate. The only clinically approved medications for ALS are Riluzole (Rilutek, Aventis Pharmaceuticals Inc.) and Edaravone (Radicava, Mitsubishi. Tanabe). Riluzole has been shown to extend survival of patients by a modest 2–3 months while a subset of patients receiving Edaravone showed a 33% reduction in the decline of their physical abilities (Dharmadasa and Kiernan, 2018; Writing and Edaravone, 2017). Despite these therapies, there is still a distinct lack
Conclusions
Although the precise pathological mechanisms behind ALS are yet to be determined, there is now increasing evidence implicating components of the complement system in the onset and progression of its motor phenotypes. Specifically, the aberrant activation or regulation of the complement system may be acting as a driving force for non-cell autonomous damage, wherein immune cell recruitment and pro-inflammatory activation causes an accelerated degeneration of motor neurons. Clinical evidence
Acknowledgements
The authors acknowledge support from the Motor Neuron Disease Research Institute of Australia (MNDRIA), the National Health and Medical Research Council (NHMRC; project grant 1082271), FightMND, Wesley Medical Research, and an Advance Queensland Innovation Partnership grant. TMW holds a NHMRC Career Development Fellowship (1105420) and JDL is also supported by a MNDRIA Postdoctoral Fellowship (PDF1604).
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