Amyotrophic lateral sclerosis: cell vulnerability or system vulnerability?

Abstract

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with clinical, pathological and genetic overlap with frontotemporal dementia (FTD). No longer viewed as one disease with a single unified cause, ALS is now considered to be a clinicopathological syndrome resulting from a complex convergence of genetic susceptibility, age-related loss of cellular homeostasis, and possible environmental influences. The rapid increase in recent years of the number of genes in which mutations have been associated with ALS has led to in vitro and in vivo models that have generated a wealth of data indicating disruption of specific biochemical pathways and sub-cellular compartments. Data implicating pathways including protein misfolding, mRNA splicing, oxidative stress, proteosome and mitochondrial dysfunction in the pathogenesis of ALS reinforce a disease model based on selective age-dependent vulnerability of a specific population of cells. To the clinical neurologist, however, ALS presents as a disease of focal onset and contiguous spread. Characteristic regional patterns of involvement and progression suggest that the disease does not proceed randomly but via a restricted number of anatomical pathways. These clinical observations combined with electrophysiological and brain-imaging studies underpin the concept of ALS at the macroscopic level as a 'system degeneration'. This dichotomy between cellular and systems neurobiology raises the fundamental questions of what initiates the disease process in a specific anatomical site and how the disease is propagated. Is the essence of ALS a cell-to-cell transmission of pathology with, for example, a 'prion-like' mechanism, or does the cellular pathology follow degeneration of specific synaptic networks? Elucidating the interaction between cellular degeneration and system level degeneration will aid modeling of the disease in the earliest phases, improve the development of sensitive markers of disease progression and response to therapy, and expand our understanding of the biological basis of clinical and pathological heterogeneity.

Keywords: C9orf72; TDP-43; amyotrophic lateral sclerosis; motor neuron disease.

Fig. 1

Primary motor neurons cultured from a transgenic mouse harbouring an ALS-associated TDP-43 mutation (M337V) (a, unstressed; b, treated with 0.5 mm sodium arsenite), demonstrating that under conditions of cellular stress TDP-43 (red) moves from the nuclear to cytoplasmic compartment, where it partially co-localises with stress granules (green) and also travels down the axon. (Courtesy of Dr David Gordon, Nuffield Department of Clinical Neurosciences, University of Oxford).

Fig. 2

Patients with ALS present to a specialist neurological clinic on average 1 year after the onset of symptoms. It is likely that this occurs when functional reserve in the motor system has been used up (vertical dotted line). Whether this occurs as an explosive loss of motor neurons on the background of normality (green line) or after a steady loss of cells over decades (blue line) is unclear. However, by analogy with other neurodegenerative diseases, it remains plausible that people who develop ALS have a period of life in which they are normal but susceptible (based on their genetic profile) followed by a period of uncertain duration in which there is system dysfunction but no clinical manifestation, either due to functional reserve within the motor system or the recruitment of active compensatory pathways.

Fig. 3

In this family, affected by ALS due to autosomal dominant inheritance of the I113T SOD1 mutation the index case (arrow) presented with typical ALS with limb onset, progression to bulbar and respiratory weakness and death within 3 years. Other family members presented with typical bulbar onset, respiratory onset or ‘creeping paralysis’, an old term for slowly progressive lower limb predominant (‘flail-leg’) ALS which typically has a survival of 5–8 years. As is common with this particular mutation, there are obligate carriers who did not develop ALS (reduced penetrance).