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The prion-like nature of amyotrophic lateral sclerosis

Journal Article


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

Publication Date


  • 2020

Citation


  • McAlary, L., Yerbury, J. J., & Cashman, N. R. (2020). The prion-like nature of amyotrophic lateral sclerosis. Unknown Journal, 175, 261-296. doi:10.1016/bs.pmbts.2020.07.002

Scopus Eid


  • 2-s2.0-85090154543

Start Page


  • 261

End Page


  • 296

Volume


  • 175

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

Publication Date


  • 2020

Citation


  • McAlary, L., Yerbury, J. J., & Cashman, N. R. (2020). The prion-like nature of amyotrophic lateral sclerosis. Unknown Journal, 175, 261-296. doi:10.1016/bs.pmbts.2020.07.002

Scopus Eid


  • 2-s2.0-85090154543

Start Page


  • 261

End Page


  • 296

Volume


  • 175