Cell-to-cell transmission of dipeptide repeat proteins linked to C9orf72-ALS/FTD

SUMMARY

Aberrant hexanucleotide repeat expansions in C9orf72 are the most common genetic change underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). RNA transcripts containing these expansions undergo repeat associated non-ATG (RAN) translation to form five dipeptide repeat proteins (DPRs). DPRs are found as aggregates throughout the CNS of C9orf72-ALS/FTD patients and some cause degeneration when expressed in vitro in neuronal cultures and in vivo in animal models. The spread of characteristic disease-related proteins drives the progression of pathology in many neurodegenerative diseases. While DPR toxic mechanisms continue to be investigated, the potential for DPRs to spread has yet to be determined. Utilizing different experimental cell culture platforms, including spinal motor neurons derived from induced pluripotent stem cells from C9orf72-ALS patients, we found evidence for cell-to-cell spreading of DPRs via exosome-dependent and independent pathways, which may potentially be relevant to disease.

Graphical abstract

eTOC:

Westergard et al. examine the cell-to-cell spread of dipeptide repeat proteins related to C9orf72-ALS/FTD in vitro and in animal models. They suggest that transcellular transmission may explain the clustered expression pattern seen in human post-mortem CNS areas as well as the progressive neurodegeneration of these diseases.