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. 2020 Nov 4:14:581907.
doi: 10.3389/fncel.2020.581907. eCollection 2020.

Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises

Luke McAlary  1   2 , Yee Lian Chew  1   2 , Jeremy Stephen Lum  1   2 , Nicholas John Geraghty  1   2 , Justin John Yerbury  1   2 , Neil R Cashman  3
Affiliations

Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises

Luke McAlary et al. Front Cell Neurosci. .

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of the motor neurons that innervate muscle, resulting in gradual paralysis and culminating in the inability to breathe or swallow. This neuronal degeneration occurs in a spatiotemporal manner from a point of onset in the central nervous system (CNS), suggesting that there is a molecule that spreads from cell-to-cell. There is strong evidence that the onset and progression of ALS pathology is a consequence of protein misfolding and aggregation. In line with this, a hallmark pathology of ALS is protein deposition and inclusion formation within motor neurons and surrounding glia of the proteins TAR DNA-binding protein 43, superoxide dismutase-1, or fused in sarcoma. Collectively, the observed protein aggregation, in conjunction with the spatiotemporal spread of symptoms, strongly suggests a prion-like propagation of protein aggregation occurs in ALS. In this review, we discuss the role of protein aggregation in ALS concerning protein homeostasis (proteostasis) mechanisms and prion-like propagation. Furthermore, we examine the experimental models used to investigate these processes, including in vitro assays, cultured cells, invertebrate models, and murine models. Finally, we evaluate the therapeutics that may best prevent the onset or spread of pathology in ALS and discuss what lies on the horizon for treating this currently incurable disease.

Keywords: amyotrophic lateral scelerosis; in vitro models; invertebrate models; mouse models; prion-like; protein aggregation; proteostasis; therapeutics.

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Figures

Figure 1
Figure 1
The relationship between proteostasis and prion-like protein propagation. (A) The proteostasis network (green objects) is composed of molecular chaperone proteins, degradation pathways (proteasomal and autophagic), and the trafficking of proteins. Chaperones act to protect vulnerable proteins from becoming misfolded and aggregating, potentially through the amyloid pathway (blue). During seed/aggregate formation, proteins vulnerable to amyloid aggregation can form polymorphic assemblies through template-directed growth, eventually, elicit different biological and pathological effects dependent on the polymorphic assembly (strain). Amyloid assemblies are thought to propagate from cell-to-cell through exocytosis in vesicles and exosomes, through membrane breakages, macropinocytosis, and tunneling nanotubes. Once an amyloid assembly has been transferred to a naive cell, replication continues as the amyloid assemblies can now recruit vulnerable protein within this cell. (B) In vitro experiments have shown that amyloid formation can be augmented via changes in environmental conditions or mutations (red) in substrate proteins to become more aggressive. Likewise, the addition of molecular chaperones and/or therapeutics (green), such as small molecules or antibodies, can suppress amyloid aggregation. (C) Amyloid aggregation in humans is a stochastic process, occurring over long time scales and, in simplistic terms, is an interplay of proteostasis capacity (green) and protein aggregation propensity (blue). Mutations and/or environmental features can result in both aggressive aggregation and/or a lower proteostasis capacity, ultimately resulting in earlier disease onset in affected individuals.
Figure 2
Figure 2
An integrative approach using purified protein to assaying the mechanisms of protein unfolding, aggregation, and prion-like behavior. Once purified, both wild-type and mutant protein is amenable to a suite of assays that can report on folding stability, function, fibrillation, and structure. Application of such techniques has allowed for the determination of the effect of the mutation on protein stability and fibrillation, the role of specific domains in fibrillation, and even the structure of fibrils themselves.
Figure 3
Figure 3
Understanding protein aggregation and prion-like spread using cultured cells. Cultured cells are amenable to genetic manipulation via transient or stable transfection, or gene editing to express fluorescently tagged wild-type or mutant forms of proteins. Cultured cells are used to study the ability of cells to uptake preformed protein aggregates in the form of purified aggregates, aggregates from other cultures, or extracts from organisms. Spreading of prion-like particles can also be assayed by serial passage of conditioned media, axonal spread through the use of microfluidic co-cultures. Furthermore, cultured cells are amenable to multiple types of omics that can provide information on wide-scale alterations to the proteome or transcriptome.
Figure 4
Figure 4
Invertebrate models of protein aggregation disorders. Invertebrate models are cheap and efficient systems that are highly amenable to genetic manipulation through the delivery of transgenes in the forms of human genes or fluorescent proteins, as well as knockout of endogenous genes. The short lifespan of these models makes them a powerful tool for assaying development and aging. Behavioral analysis can be performed to determine the effect of protein aggregation in these models, linking observed pathology to clinical phenotypes. Last, these models are highly accessible to imaging and provide access to well-understood neuroanatomy to assay prion-like spread.
Figure 5
Figure 5
Murine models of protein aggregation and prion-like propagation. Murine models form the crux of our pathobiological understanding of the effects of protein aggregation and prion-like propagation in mammals. This is due to their genetic similarity with humans, which translates into similar physiology, similar disease susceptibility, and similar neuroanatomy. The input of disease-associated genes into mice often results in similar clinicopathological features including behavioral deficits, protein aggregation, and loss of neurons in specific tissues. Prion-like propagation can be assayed through the injection of seed protein aggregates into specific locations, and the passage of extracted prion-like seeds can be used to define strains. Finally, these models are the gateway to the clinic and are mostly used for the testing of drugs and therapies that are aimed at alleviating human disease.
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