Intercellular transmission of pathogenic proteins in ALS: Exploring the pathogenic wave

F J Arnold; A D Nguyen; R S Bedlack; C L Bennett; A R La Spada

doi:10.1016/j.nbd.2023.106218

Intercellular transmission of pathogenic proteins in ALS: Exploring the pathogenic wave

Neurobiol Dis. 2023 Aug:184:106218. doi: 10.1016/j.nbd.2023.106218. Epub 2023 Jun 30.

Authors

F J Arnold¹, A D Nguyen², R S Bedlack², C L Bennett³, A R La Spada⁴

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, USA; Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA.
² Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA.
³ Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, USA; Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: craiglb@uci.edu.
⁴ Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, USA; Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA; Departments of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA; Department of Neurology, University of California, Irvine, Irvine, CA, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; UCI Center for Neurotherapeutics, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: alaspada@uci.edu.

PMID: 37394036
DOI: 10.1016/j.nbd.2023.106218

Abstract

In patients with amyotrophic lateral sclerosis (ALS), disease symptoms and pathology typically spread in a predictable spatiotemporal pattern beginning at a focal site of onset and progressing along defined neuroanatomical tracts. Like other neurodegenerative diseases, ALS is characterized by the presence of protein aggregates in postmortem patient tissue. Cytoplasmic, ubiquitin-positive aggregates of TDP-43 are observed in approximately 97% of sporadic and familial ALS patients, while SOD1 inclusions are likely specific to cases of SOD1-ALS. Additionally, the most common subtype of familial ALS, caused by a hexanucleotide repeat expansion in the first intron of the C9orf72 gene (C9-ALS), is further characterized by the presence of aggregated dipeptide repeat proteins (DPRs). As we will describe, cell-to-cell propagation of these pathological proteins tightly correlates with the contiguous spread of disease. While TDP-43 and SOD1 are capable of seeding protein misfolding and aggregation in a prion-like manner, C9orf72 DPRs appear to induce (and transmit) a 'disease state' more generally. Multiple mechanisms of intercellular transport have been described for all of these proteins, including anterograde and retrograde axonal transport, extracellular vesicle secretion, and macropinocytosis. In addition to neuron-to-neuron transmission, transmission of pathological proteins occurs between neurons and glia. Given that the spread of ALS disease pathology corresponds with the spread of symptoms in patients, the various mechanisms by which ALS-associated protein aggregates propagate through the central nervous system should be closely examined.

Keywords: ALS; Cell-to-cell propagation; Endocytosis; Extracellular-vesicles; Oligomerization.

Publication types

Review

MeSH terms

Amyotrophic Lateral Sclerosis* / metabolism
C9orf72 Protein / genetics
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Humans
Protein Aggregates
Superoxide Dismutase-1 / metabolism

Substances

Superoxide Dismutase-1
Protein Aggregates
C9orf72 Protein
DNA-Binding Proteins

Supplementary concepts

Amyotrophic lateral sclerosis 1