Decoding ALS: from genes to mechanism

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and uniformly fatal neurodegenerative disease. A plethora of genetic factors have been identified that drive the degeneration of motor neurons in ALS, increase susceptibility to the disease or influence the rate of its progression. Emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking, the induction of stress at the endoplasmic reticulum and impaired dynamics of ribonucleoprotein bodies such as RNA granules that assemble through liquid-liquid phase separation. Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified.

Figure 1. The components of the nervous system impacted in ALS

(a) ALS primarily impacts descending corticospinal motor neurons (upper motor neurons) that project from the motor cortex to synapses in the brainstem and spinal cord, and bulbar or spinal motor neurons (lower motor neurons) that project to skeletal muscles. (b) Typical pathology of different ALS subtypes. Clockwise from top left: SOD1 aggregates in spinal motor neurons in SOD1-related familial ALS; TDP-43 redistribution to cytoplasmic inclusions in spinal motor neurons in sporadic ALS; GR dipeptide repeat pathology in the dentate nucleus of C9-ALS/FTD; GA dipeptide repeat pathology in the dentate nucleus of C9-ALS/FTD; RNA foci in the nucleus (arrows) and cytoplasm (arrowhead) of a cortical neuron in C9-ALS/FTD.

Figure 2. Schematic representation of the major cellular disease mechanisms implicated in ALS

(a) Disturbances in protein quality control and ER stress. (b) Microglial activation and production of extracellular superoxide. (c) Reduced energy supply from oligodendrocytes to the underlying motor axons following reduced levels of the MCT1 lactate transporter. (d) Release from astrocytes of an as-yet unidentified species toxic to motor neurons. (e) Disruption of the cytoskeleton and impaired axonal transport. (f) Disturbance of multiple aspects of RNA metabolism are implicated in ALS.

Figure 3. ALS mutations impair the assembly, dynamics and function of membrane-less organelles such as RNA granules

(a) Schematic representation of six hnRNPs that harbor mutations causative of a disease spectrum that ranges from ALS/FTD to myopathy. (b) Phase separation by the RNA-binding protein hnRNPA1. RNA-binding proteins with a LCD can transition from a single mixed phase to two distinct phases, one of which is a concentrated liquid droplet. (c) Phase separation contributes to the assembly, dynamics and liquid properties of membrane-less organelles such as RNA granules. Within RNA granules, the high concentration and close apposition of LCDs risks transition to amyloid-like fibrils, which likely provides the source for pathological deposition of proteins particularly prone to fibrillization, such as TDP-43.

Figure 4. Three non-exclusive mechanisms have been proposed for C9-ALS/FTD

The offending mutation is expansion of a hexanucleotide repeat (GGGGCC) from fewer than 23 to hundreds or thousands in C9-ALS/FTD patients. This mutation results in modest reduction of C9ORF72 protein that appears insufficient to cause disease but may contribute to disease progression. Expression of sense and antisense transcripts containing the expanded repeat likely drive a toxic gain of function. The two major modes of toxic gain of function implicated are (1) toxicity of the mutant transcript, perhaps through sequestration of RNA-binding proteins, and (2) unconventional translation to produce dipeptide repeat proteins, some of which may be toxic.