Abstract
The discovery that prion protein can misfold into a pathological conformation that encodes structural information capable of both propagation and inducing severe neuropathology has revolutionized our understanding of neurodegenerative disease. Many neurodegenerative diseases with a protein misfolding component are now classified as “prion-like” owing to the propagation of both symptoms and protein aggregation pathology in affected individuals. The neuromuscular disorder amyotrophic lateral sclerosis (ALS) is characterized by protein inclusions formed by either TAR DNA-binding protein of 43 kDa (TDP-43), Cu/Zn superoxide dismutase (SOD1), or fused in sarcoma (FUS), in both upper and lower motor neurons. Evidence from in vitro, cell culture, and in vivo studies has provided strong evidence to support the involvement of a prion-like mechanism in ALS. In this article, we review the evidence suggesting that prion-like propagation of protein aggregation is a primary pathomechanism in ALS, focusing on the key proteins and genes involved in disease (TDP-43, SOD1, FUS, and C9orf72). In each case, we discuss the evidence ranging from biophysical studies to in vivo examinations of prion-like spreading. We suggest that the idiopathic nature of ALS may stem from its prion-like nature and that elucidation of the specific propagating protein assemblies is paramount to developing effective therapies.
Highlights
The discovery that prion protein can misfold into a pathological conformation that encodes structural information capable of both propagation and inducing severe neuropathology has revolutionized our understanding of neurodegenerative disease
We review the evidence suggesting that prion-like propagation of protein aggregation is a primary pathomechanism in amyotrophic lateral sclerosis (ALS), focusing on the key proteins and genes involved in disease (TDP-43, Superoxide dismutase-1 (SOD1), fused in sarcoma (FUS), and chromosome 9 open reading frame 72 (C9orf72))
Protein misfolding is defined as the adoption of a non-native conformation by a protein; Protein aggregation is the aberrant accumulation of a protein into multimeric soluble or insoluble non-native structures; Protein deposition is the formation of large insoluble deposits of proteins (Chiti and Dobson, 2017)
Summary
Classical understanding of progressive and infectious diseases mandated that a nucleic acid component be present to facilitate replication of the infectious particles This idea has since been challenged owing to the discovery that a class of neurological disorders, known as the prion diseases, possess an infectious life cycle and spread in the CNS in the absence of any microbial nucleic acid component. PrPSc was found to be able to catalyze the misfolding of PrPC, generating more conformational copies of PrPSc that can spread throughout cells, tissues, and even between organisms. This notion of the propagation of protein misfolding has been subsequently applied to neurodegenerative diseases, providing a possible explanation for the protein aggregation pathology and progressive spatiotemporal degeneration observed in these diseases. The neuropathological similarities of prion diseases with other neurodegenerative diseases include substantial neuronal loss, accumulation of proteins into aggregates, gliosis, and general cerebral atrophy (Prusiner, 2001)
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