Amyotrophic lateral sclerosis (ALS) pathway

It’s essential that cells balance the rates of synthesis and degradation of different proteins: proper protein homeostasis ensures that cells survive and perform their intended functions. Proteome imbalance in motor neurons leads to functional defects: changes in excitability, mitochondrial dysfunction, endoplasmic reticulum stress, and protein aggregation³. Ultimately, the results of proteome imbalance lead to cell death.

There’s strong evidence that proteome imbalance is a core feature of ALS: C9orf72, SOD1 FUS, and TARDBP, four of the most commonly implicated genes in ALS, are involved in proteome homeostasis³.

As well as the genetic implications, ALS’ hallmark feature of protein aggregate deposits indicates impaired protein degradation. Finally, motor neurons are particularly vulnerable to proteome stress, owing primarily to their huge size.

Dysregulation of autophagy and the proteasome have been classically thought to be front and center in ALS: SOD1 mutations impair proteasome function, and C9orf72, the most common mutation in familial ALS, is a key autophagy regulator. However, more recent research implicates dysregulation in protein production and folding too: mutations in several RNA binding proteins, including TARDBP and FUS, are associated with ALS⁴.

Glutamate excitotoxicity, where cells die due to excess intracellular calcium caused by excessive stimulation of AMPA receptors by glutamate, is common to all forms of ALS. Motor neurons are susceptible to excitotoxicity as the AMPA receptors found in motor neurons are relatively deficient in the GluR2 subunit (in both healthy and ALS cells)^5,6.

The amount of glutamate in the presynaptic space, and therefore the degree of excitotoxicity, is worsened in ALS by decreased levels of the glutamate transporter EAAT2 on astrocytes (see later). Excitotoxicity is also worsened by oxidative stress.

Oxidative stress is implicated in the loss of motor neurons and in propagating mitochondrial dysfunction and neurodegeneration. Mitochondrial function is impaired in ALS, and evidence of increased oxidative stress has been found in both familial and sporadic ALS⁷. While oxidative stress is found in many neurodegenerative disorders, the large size and high metabolic demand of motor neurons means that oxidative stress plays a key role in ALS. SOD1, one of the key genes mutated in ALS, is a metalloenzyme that usually reduces the amount of superoxide in neurons; mutations in SOD1 are associated with oxidative stress in ALS⁷.

As well as causing neurodegeneration, oxidative stress drives excitotoxicity: oxidative damage causes reduced glutamate binding to transporters, increasing AMPA binding and driving calcium influx. Conversely, excitotoxicity drives further oxidative stress: calcium ions enter mitochondria, causing increased production of reactive oxygen species. 

Motor neurons have historically dominated ALS research, but recently the role of glia has been explored in greater focus. In ALS, microglia undergo functional changes, either neuroprotective – producing anti-inflammatory and neurotrophic factors – or neurotoxic, producing pro-inflammatory cytokines, contributing to reactive oxygen species production, and activating astrocytes to a neurotoxic state⁸. It’s thought that reactive oxygen species may drive the switch to neurotoxicity, activating microglia and promoting the spread of neuronal degeneration.

Activated astrocytes found in ALS produce pro-inflammatory cytokines and reactive oxygen species, decrease secretion of neurotrophic factors and contribute to excitotoxicity by reducing their rate of glutamate reuptake. It’s hoped that greater research into the role of glia in ALS progression may yield more avenues for therapeutics.