Phenotypic diversity in ALS and the role of poly-conformational protein misfolding
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REVIEW
Phenotypic diversity in ALS and the role of poly‑conformational protein misfolding Jacob I. Ayers1 · David R. Borchelt2 Received: 12 June 2020 / Revised: 30 August 2020 / Accepted: 30 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract In many types of familial amyotrophic lateral sclerosis (fALS), mutations cause proteins to gain toxic properties that mediate neurodegenerative processes. It is becoming increasingly clear that the proteins involved in ALS, and those responsible for a host of other neurodegenerative diseases, share many characteristics with a growing number of prion diseases. ALS is a heterogenous disease in which the majority of cases are sporadic in their etiology. Studies investigating the inherited forms of the disease are now beginning to provide evidence that some of this heterogeneity may be due to the existence of distinct conformations that ALS-linked proteins can adopt to produce the equivalent of prion strains. In this review, we discuss the in vitro and in vivo evidence that has been generated to better understand the characteristics of these proteins and how their tertiary structure may impact the disease phenotype. Keywords Amyotrophic lateral sclerosis · Superoxide dismutase-1 · TDP-43 · Prion · Strains
Introduction Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to paralysis and ultimately death of those afflicted with the condition. Although weakness can first appear anywhere in the body, including the respiratory system, most cases manifest in limb or bulbar muscles as a focal weakness before spreading throughout the motor axis to weaken respiratory muscles. This muscle loss is caused by the degeneration of both upper and lower motor neurons throughout the CNS, and, unfortunately, there are no treatments that slow disease progression or significantly lengthen survival. The prevalence of ALS is about five cases per 100,000 with an incidence of 1–2 individuals diagnosed per 100,000 each year, revealing how quickly the disease progresses. The majority of cases are fatal within 2–4 years after diagnosis, but factors such * Jacob I. Ayers [email protected] 1
Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA 94143, USA
Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA
2
as the site of onset, duration from first symptom to diagnosis, presence of cognitive impairment, and genotype can increase survival to more than 10 years after onset [1, 29]. The motor dysfunction in ALS has also been demonstrated to overlap with frontotemporal dementia (FTD), a disease characterized by the degeneration of the frontal and temporal lobes. Up to 50% of patients with ALS develop frontal lobe dysfunction, whereas approximately 15% of patients with FTD develop motor neuron loss. Although clinically indistinguishable, ~ 90% of ALS cases are sporadic
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