Chapter Eleven - The prion-like nature of amyotrophic lateral sclerosis

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Abstract

The misfolding, aggregation, and deposition of specific proteins is the key hallmark of most progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). ALS is characterized by the rapid and progressive degenerations of motor neurons in the spinal cord and motor cortex, resulting in paralysis of those who suffer from it. Pathologically, there are three major aggregating proteins associated with ALS, including TAR DNA-binding protein of 43 kDa (TDP-43), superoxide dismutase-1 (SOD1), and fused in sarcoma (FUS). While there are ALS-associated mutations found in each of these proteins, the most prevalent aggregation pathology is that of wild-type TDP-43 (97% of cases), with the remaining split between mutant forms of SOD1 (~ 2%) and FUS (~ 1%). Considering the progressive nature of ALS and its association with the aggregation of specific proteins, a growing notion is that the spread of pathology and symptoms can be explained by a prion-like mechanism. Prion diseases are a group of highly infectious neurodegenerative disorders caused by the misfolding, aggregation, and spread of a transmissible conformer of prion protein (PrP). Pathogenic PrP is capable of converting healthy PrP into a toxic form through template-directed misfolding. Application of this finding to other neurodegenerative disorders, and in particular ALS, has revolutionized our understanding of cause and progression of these disorders. In this chapter, we first provide a background on ALS pathology and genetic origin. We then detail and discuss the evidence supporting a prion-like propagation of protein misfolding and aggregation in ALS with a particular focus on SOD1 and TDP-43 as these are the most well-established models in the field

Section snippets

Neurodegenerative diseases are associated with protein misfolding and aggregation

Neurodegenerative diseases are characterized by the progressive loss of neuronal cells in the central nervous system (CNS) and typically occur in older individuals.1 The major neurodegenerative disorders are Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies, spinocerebellar ataxia, frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Huntington's disease.2 In concordance with neuronal loss, symptoms can

Prion diseases are clinically and pathologically similar to other neurodegenerative diseases

Prion diseases are a set of incurable progressive neurodegenerative disorders which includes Creutzfeldt-Jakob disease (CJD), fatal familial insomnia, kuru, bovine spongiform encephalopathy, and others.18 CJD is the most common prion disease, and similar to other age-related neurodegenerative diseases it can occur sporadically or within genetic lineages, and it also primarily affects individuals later in life.19, 20

Clinically, prion diseases are associated with rapid and significant decline in

Prions and prion-like proteins—An important distinction

The hypothesis that a protein could be self-replicating and infectious in the absence of nucleic acids was first proposed in the 1960s,28, 29 however, it was not until 1982 that the culprit protein was isolated by Prusiner.27 Prusiner named the newly isolated protein as a “prion” for protein infectious particle and the protein itself became known as prion protein (PrP) after the protein was discovered to be normally physiologically expressed. Subsequent research that established that the normal

Amyotrophic lateral sclerosis—Spread and progression of clinical symptoms

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease or Lou Gehrig's disease, is an ultimately fatal neuromuscular disorder in which motor neurons preferentially and progressively degenerate, leading to paralysis. Diagnosis of a patient with ALS is devastating to emotional well-being due to the nature of the disease leaving the patient fully aware of the decline in their autonomy, which in combination with the lack of any effective treatment often results in an aggressive

Amyotrophic lateral sclerosis—Pathological manifestation

ALS shares many pathological features with other neurodegenerative diseases, such as the degeneration of neuronal cells within the CNS and the deposition of proteins into inclusion bodies, however, the manifestation of pathology can be both morphologically and biochemically heterogeneous. The ALS-associated inclusion types includes spheroids, hyaline inclusions, skein-like inclusions, basophilic inclusions, and bunina bodies (reviewed in Ref. 55). This difference in inclusion morphology

Amyotrophic lateral sclerosis—Diversity of associated genes

Similar to the diverse morphological and biochemical properties of the pathological inclusions in ALS, there is a large and growing, diverse set of genes found to be ALS-associated.71 Stratification of these ALS-associated genes yields three major processes that may play a role in disease pathogenesis including RNA metabolism, protein quality control, and cytoskeletal dynamics/transport (Table 1). These processes do not occur independently from one another, but rather represent a global

Prion protein and ALS-associated proteins are capable of forming amyloidogenic assemblies

Amyloid fibrils composed of disease-associated proteins are intimately linked with neurodegenerative disease.7, 104, 105 Amyloid fibrils are characterized by their cross-β spine structure that typically spans 7–13 nm and their ability to bind certain dyes such as thioflavin-T and Congo red, although there are cases where thioflavin-T binding is negative but fibrils can be observed via electron microscopy.106 A great deal of effort has been applied to understand the processes that underpin the

Cu/Zn superoxide dismutase has pathological prion-like properties in vitro and in vivo

SOD1 was the first gene found to carry ALS-associated mutations72 and as such is the most well studied where now there are over 160 known mutations associated with ALS.120 The primary cellular role of SOD1 is to catalyze the dismutation of superoxide anion to less harmful hydrogen peroxide or molecular oxygen.121 The enzymatic activity of SOD1 is dependent on its ability to fold into its native state, a process which requires zinc-binding, copper-binding, the formation of an intramolecular

TAR DNA-binding protein of 43 kDa has pathological prion-like properties in vitro and in vivo

The finding that TDP-43 was the primary ubiquitinated protein observed in the majority of ALS patients shifted the research focus from SOD1 onto this DNA/RNA-binding protein. As a DNA/RNA-binding protein, TDP-43 has many roles within the cell related to RNA regulation and processing183, 184, 185, 186, 187 and some of these are essential for development as knockout of TDP-43 is embryonic lethal.188, 189, 190 TDP-43 is primarily localized to the nucleus, however, it can shuttle between the

Fused in sarcoma has only modest evidence to suggest its pathological prion-like propagation in ALS

Fused in sarcoma (FUS) is similar to TDP-43 in that it is an RNA/DNA-binding protein with roles in RNA metabolism, transport, and DNA repair.223, 224 Structurally, FUS contains an N-terminal functional PrLD, several RGG rich regions, an RRM, a zinc finger motif, and a C-terminal nuclear localization signal, where all of these features make it a member of the TET protein family.225 ALS and FTLD-associated mutations are clustered into the first RGG rich domain and the C-terminal NLS,16, 17 and as

Conclusions

It is clear that ALS has all the hallmarks of a pathological prion-like disease in which the initiation and spread protein misfolding and aggregation is a key feature of disease etiology and progression.215 There is strong evidence supporting the pathological prion-like characteristics of SOD1 and TDP-43, however, the evidence supporting a similar role for FUS is less clear and it remains to be established if FUS is acting in a pathological prion-like manner in ALS. Nevertheless, the majority

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