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Cold Spring Harb Perspect Med. 2017 Nov 1;7(11). pii: a024133. doi: 10.1101/cshperspect.a024133.

Biological Spectrum of Amyotrophic Lateral Sclerosis Prions.

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Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, 9500 Gilman Drive, San Diego, La Jolla, California 92093-0670.


Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) are two neurodegenerative diseases with distinct clinical features but common genetic causes and neuropathological signatures. Ten years after the RNA-binding protein TDP-43 was discovered as the main protein in the cytoplasmic inclusions that characterize ALS and FTLD, their pathogenic mechanisms have never seemed more complex. Indeed, discoveries of the past decade have revolutionized our understanding of these diseases, highlighting their genetic heterogeneity and the involvement of protein-RNA assemblies in their pathogenesis. Importantly, these assemblies serve as the foci of protein misfolding and mature into insoluble structures, which further recruit native proteins, turning them into misfolded forms. This self-perpetuating mechanism is a twisted version of classical prion replication that leads to amplification of pathological protein complexes that spread throughout the neuraxis, offering a pathogenic principle that underlies the rapid disease progression that characterizes ALS and FTLD.

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