Revisiting the role of the innate immune complement system in ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease without effective treatment. Although the precise mechanisms leading to ALS are yet to be determined, there is now increasing evidence implicating components of the innate immune complement system in the onset and progression of its motor phenotypes. This review will survey the clinical and experimental evidence for the role of the complement system in driving neuroinflammation and contributing to ALS disease progression. Specifically, it will explore findings regarding the different complement activation pathways involved in ALS, with a focus on the terminal pathway. It will also examine potential future research directions for complement in ALS, highlighting the targeting of specific molecular components of the system.

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.