Pathomechanistic Networks of Motor System Injury in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is the most common, adult-onset, progressive motor neurodegenerative disorder that results in death within 3 years of the clinical diagnosis. Due to the clinicopathological heterogeneity, any reliable biomarkers for diagnosis or prognosis of ALS have not been identified till date. Moreover, the only three clinically approved treatments are not uniformly effective in slowing the disease progression. Over the last 15 years, there has been a rapid advancement in research on the complex pathomechanistic landscape of ALS that has opened up new avenues for successful clinical translation of targeted therapeutics. Multiple studies suggest that the age-dependent interaction of risk-associated genes with environmental factors and endogenous modifiers is critical to the multi-step process of ALS pathogenesis. In this review, we provide an updated discussion on the dysregulated cross-talk between intracellular homeostasis processes, the unique molecular networks across selectively vulnerable cell types, and the multisystemic nature of ALS pathomechanisms. Importantly, this work highlights the alteration in epigenetic and epitranscriptomic landscape due to gene-environment interactions, which have been largely overlooked in the context of ALS pathology. Finally, we suggest that precision medicine research in ALS will be largely benefitted from the stratification of patient groups based on the clinical phenotype, onset and progression, genome, exposome, and metabolic identities.

Keywords: Amyotrophic lateral sclerosis (ALS); RNA modification.; epigenetics; gene environment interaction; heterogeneity; metabolism; motor neuron disease; pathophysiology.

Fig. (1)

Pattern of the motor system dysfunction in ALS. Progressive degeneration affects the vulnerable fast-fatigable (FF) motor neurons and type IIb myofibres. Slow twitch (S) motor neurons and type I myofibres are resilient until the end stages. A ‘dying forward’ hypothesis proposes an anterograde degenerative trigger from cortex progresses towards spinal cord through trans-synaptic glutamate excitotoxicity. LMNs without a monosynaptic connection to corticomotor neurons are resilient to ALS pathology such as oculomotor, abducens, trochlear nerve, and Onuf's nuclei. A ‘dying back’ hypothesis suggests that an early retrograde degeneration trigger from neuromuscular junctions (NMJs) moves back towards primary motor cortex by distal axonopathy. Both UMN and LMN degeneration can also occur independently and in a stochastic manner during ALS progression, which might be attributed to oxidative stress mediated apoptosis. Reprinted from N Engl J Med 377:2, Brown, R.H.; Al-Chalabi, A., Amyotrophic Lateral Sclerosis, 162-172, Copyright (2017), with permission from (Massachusetts Medical Society).

Fig. (2)

Complex interplay of molecular networks in ALS pathogenesis. Mislocalization and aggregation of misfolded proteins dysregulate RNA metabolism as well as stress granule dynamics, which in turn induces endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, and DNA damage. Overexpression of Ca²⁺ -permeable glutamate receptors in postsynaptic neurons, and increased glutamate release by presynaptic neurons and astrocytes is associated with decreased glutamate reuptake from synapse. Concomitant synaptic stripping of the inhibitory connections triggers sustained neuronal firing that results in excitotoxicity. Chemokines released from the affected neurons and reactive astroglia promote necroptosis of oligodendrocytes with subsequent demyelination.

Fig. (3)

A multi-network and non-cell autonomous failure of cellular homeostasis processes drives ALS. Misfolded protein aggregates induce defects in the intracellular homeostasis processes, which in turn disrupts the protective neuron-astroglia crosstalk. Concomitantly, the defects in synaptic scaling and plasticity of motor neurons results in glutamate excitotoxicity. Release of neuron-specific antigens and proinflammatory stimuli primes T-helper cells into a proinflammatory Th17 phenotype for recruitment into the central nervous system. Side by side, infiltration of cytotoxic T-cells and natural killer cells occurs through adaptive immune signalling. Defective axonal transport hinders the cholinergic transmission towards neuromuscular junctions and impairs myofibre contractility. Release of growth-cone repellents from skeletal muscles and chemorepellents from dying terminal Schwann cells triggers distal axonopathy.

Fig. (4)

Changes in the epigenetic and epitranscriptomic landscape during ALS pathogenesis. ALS-associated epigenetic signatures include a global increase in DNA methylation with a concomitant deregulation of DNA methyltransferases (DNMTs). A global decrease in histone acetylation is concomitant with a dysregulation of histone acetyltransferases and histone deacetylases (HDACs). Global dysregulation of miRNA levels includes their sequestration in stress granules by mutant protein aggregates. ALS-relevant epitranscriptomic modifications commonly involves A-to-I editing defect in GluA2 transcript, which upregulates Ca²⁺ -permeable glutamate receptor in neurons. Accumulation of ROS-induced oxidized mRNA species, and tRNA fragment cleaved by mutant ANG impairs protein translation efficiency. Aberrant intron-retaining transcripts promote mislocalization of RNA binding proteins. Abbreviations: CHD2: chromodomain DNA helicase protein 2; CBP/p300: CREB binding protein p300; EAAT2: excitatory amino acid transporter 2; nBAF: neuronal Brg1-associated factor; PRMT1: protein arginine methyltransferase 1; SIRT: sirtuin; SFPQ: splice factor proline glutamine rich.