Chapter 18 - Prion-like mechanisms in amyotrophic lateral sclerosis

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Abstract

The prion hypothesis – a protein conformation capable of replicating without a nucleic acid genome – was heretical at the time of its discovery. However, the characteristics of the disease-misfolded prion protein and its ability to transmit disease, replicate, and spread are now widely accepted throughout the scientific community. In fact, in the last decade a wealth of evidence has emerged supporting similar properties observed for many of the misfolded proteins implicated in other neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, tauopathies, and as described in this chapter, amyotrophic lateral sclerosis (ALS). Multiple studies have now demonstrated the ability for superoxide dismutase-1, 43-kDa transactive response (TAR) DNA-binding protein, fused-in sarcoma, and most recently, C9orf72-encoded polypeptides to display properties similar to those of prions. The majority of these are cell-free and in vitro assays, while superoxide dismutase-1 remains the only ALS-linked protein to demonstrate several prion-like properties in vivo. In this chapter, we provide an introduction to ALS and review the recent literature linking several proteins implicated in the familial forms of the disease to properties of the prion protein.

Introduction

Amyotrophic lateral sclerosis (ALS) is a devastating and ultimately fatal disease characterized by progressive paralysis caused by the degeneration of both upper and lower motor neurons in the brain, brainstem, and spinal cord. It is considered an orphan disease with an incidence of 1–2 individuals diagnosed per 100,000 each year and a prevalence of only about 5 cases per 100,000, revealing the rapidity of the disease, which in about 80% of cases is fatal within 3–5 years after diagnosis (Al-Chalabi and Hardiman, 2013). The mean age of disease onset is 55 years of age, but varies dramatically, with some cases beginning in an individual's 20s or as late as their 80s. This large variability in disease characteristics is also observed in the degree of upper vs. lower motor neuron involvement, and where the symptoms first manifest themselves (e.g., arm(s), leg(s), or bulbar) (Grad et al., 2016). Limb or bulbar muscle weakness usually begins focally before progressively spreading throughout the entire voluntary motor system, with typically late involvement of respiratory muscles. Although historically believed to cause a pure motor system degeneration, within the last 20 years clinical evidence has demonstrated cognitive impairment and a strong overlap of symptomology with frontotemporal degeneration (FTD), a disease caused by neuronal degeneration in the frontal and temporal lobes (Goldstein and Abrahams, 2013). The cognitive deficits can have a substantial negative impact on the disease phenotype and this is correlated with a decreased survival rate in patients (Olney et al., 2005).

Approximately 10% of ALS cases occur in multiple individuals within a family (familial ALS, or fALS), while the majority of cases present without any evidence of inheritance and are termed sporadic ALS (sALS). Clinically, fALS and sALS are essentially indistinguishable from one another. Mutations in the gene encoding SOD1 were the first to be identified as a hereditary cause of ALS in 1993 (Rosen et al., 1993), and since then, mutations in more than 50 other genes have been implicated in ALS pathogenesis. However, many of these have yet to be completely validated. Genes that have consistently revealed linkage to a significant percentage of fALS cases include those encoding the 43-kDa transactive response (TAR) DNA-binding protein (TDP-43), fused-in sarcoma/translocated in liposarcoma (FUS/TLS), ubiquilin-2, senataxin, and C9ORF72 (http://alsod.iop.kcl.ac.uk/). Although mutations within these genes cause a disease clinically and pathologically consistent with the ALS syndrome, the wild-type (WT) proteins encoded by these mutation-validated genes have a diverse set of functions, including transcription control and splicing regulation via RNA binding, proteostasis and protein quality control, and cytoskeleton support and axon development. For this reason, some believe that there is a common, as of yet unknown, pathogenic mechanism underlying all ALS.

Prion diseases consist of a number of human and animal diseases characterized by widespread neuronal loss and spongiosis in the central nervous system (CNS). These diseases are caused by the infectious prion protein, an abnormal isoform of the host-encoded normal cellular prion protein. At the time of its discovery, and for decades thereafter, the prion protein was believed to be unique in its engagement in the templated propagation mechanism of prion infectivity. More recently, a wealth of research supports the notion that other diseases caused by misfolded proteins share characteristics with prion diseases, including Alzheimer disease, Parkinson disease, Huntington disease, and ALS, among others (Guest et al., 2011) (Table 18.1). Some of the proteins implicated in these diseases undergo a gain of toxic properties and demonstrate the ability for conformational templating, cell-to-cell and neuroanatomic spread, and to exist in conformationally distinct species or “strains” (Clavaguera et al., 2009; Jucker and Walker, 2013; Sacino et al., 2013; Sanders et al., 2014; Watts et al., 2014; Peelaerts et al., 2015).

Section snippets

SOD1

The copper zinc superoxide dismutase-1 (SOD1) protein is an antioxidant enzyme that functions in the disproportionation of highly reactive superoxide to generate hydrogen peroxide and dioxygen. SOD1 exists as an extremely stable homodimer in which each subunit contains one copper and one zinc ion along with an intra-subunit disulfide bond (Parge et al., 1992; Ogihara et al., 1996). It is an abundant protein, localized primarily in the cytosol (Crapo et al., 1992), but has also been observed

Propagation and seeding of SOD1

Research into the properties of the prion protein and its associated disorders revealed unique properties of the infectious agent that had never before been observed for a mammalian protein, and questioned the central dogma of infectious agents; that replication required a nucleic acid genome. The most profound, and at the time controversial, finding was that of the “protein-only” hypothesis, which states that the infectious agent responsible for these diseases, PrPTSE, is produced via a

Spreading of ALS symptoms and pathology

For classic prions, it is well established that the infectious agent is capable of spreading throughout the CNS via neuroanatomic pathway connections. The first evidence of this came about through intraocular inoculation of homogenates in mice, in which the temporal and spatial accumulation of spongiosis was found to be consistent with axonal transport along the retinotectal pathway (Fraser, 1982). This characteristic is a hallmark of prion diseases and one that is suggested to play a role in

Existence of ALS-inducing protein strains

During the early years of prion research it was believed that the infectious agent was a slow-acting virus (Gajdusek, 1977). Although heretical at its time, it was later revealed that the agent contains no nucleic acid and exists as an abnormal conformer of a normal, host-encoded protein (Prusiner, 1982). One reason that the hypothesis of a protein-only infectious agent was not well accepted at the time was because a variety of prion isolates displayed distinct and highly reproducible

Potential role for WT SOD1 in ALS pathogenesis

Based on the similarities in disease phenotypes between SOD1-fALS and sALS, questions have been raised concerning the potential pathogenic role that WT SOD1 could play in sALS. If such a role were uncovered, it would have important implications in providing scientific investigators with a therapeutic target for treating the major proportion of all ALS that sALS comprises. In fact, there are currently a number of clinical trials under way to determine the efficacy of various treatments aimed at

Conclusions

At the time of its discovery, the concept of a protein conformation capable of replicating and inducing a heritable conformational change without the need for a nucleic acid genome was heretical. However, the characteristics of the disease-misfolded prion protein and its ability to transmit disease, replicate, and spread are now widely accepted throughout the scientific community. In fact, in the last decade a wealth of evidence has emerged supporting similar properties observed for many of the

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