Journal Article

C9orf72-Associated Dipeptide Repeat Expansions Perturb ER-Golgi Vesicular Trafficking, Inducing Golgi Fragmentation and ER Stress, in ALS/FTD

Deva, Anand, Yang, Shu, Nicholson, Garth, Shadfar, Sina, Rowe, Dominic B., Ragagnin, Audrey M. G., Atkin, Julie D., Sultana, Jessica, Vidal, Marta, Jagaraj, Cyril Jones, Blair, Ian, Saravanabavan, Sayanthooran, Parakh, Sonam, Don, Emily K., Soo, Kai Ying, Ding, Kunjie, Wu, Sharlynn

2024

Overview

Hexanucleotide repeat expansions (HREs) in the chromosome 9 open reading frame 72 ( C9orf72 ) gene are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both are debilitating neurodegenerative conditions affecting either motor neurons (ALS) in the brain and spinal cord or neurons in the frontal and/or temporal cortical lobes (FTD). HREs undergo repeat-associated non-ATG (RAN) translation on both sense and anti-sense strands, generating five distinct dipeptide repeat proteins (DPRs), poly-GA, -GR, -GP, -PA and -PR. Perturbed proteostasis is well-recognised in ALS pathogenesis, including processes affecting the endoplasmic reticulum (ER) and Golgi compartments. However, these mechanisms have not been well characterised for C9orf72-mediated ALS/FTD. In this study we demonstrate that C9orf72 DPRs polyGA, polyGR and polyGP (× 40 repeats) disrupt secretory protein transport from the ER to the Golgi apparatus in neuronal cells. Consistent with this finding, these DPRs also induce fragmentation of the Golgi apparatus, activate ER stress, and inhibit the formation of the omegasome, the precursor of the autophagosome that originates from ER membranes. We also demonstrate Golgi fragmentation in cells undergoing RAN translation that express polyGP. Furthermore, dysregulated ER-Golgi transport was confirmed in C9orf72 patient dermal fibroblasts. Evidence of aberrant ER-derived vesicles in spinal cord motor neurons from C9orf72 ALS patients compared to controls was also obtained. These data thus confirm that ER proteostasis and ER-Golgi transport is perturbed in C9orf72-ALS in the absence of protein over-expression. Hence this study identifies novel molecular mechanisms associated with the ER and Golgi compartments induced by the C9orf72 HRE.

• Publisher: Springer US,Springer Nature B.V
• Subject: Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Axonal transport / Biomedical and Life Sciences / Biomedicine / C9orf72 Protein - genetics / C9orf72 Protein - metabolism / Cell Biology / Chromosome 9 / Dementia disorders / Dipeptides - metabolism / DNA Repeat Expansion - genetics / Endoplasmic reticulum / Endoplasmic Reticulum - metabolism / Endoplasmic Reticulum Stress - genetics / Frontotemporal dementia / Frontotemporal Dementia - genetics / Frontotemporal Dementia - metabolism / Frontotemporal Dementia - pathology / Golgi Apparatus - metabolism / Humans / Molecular modelling / Motor neurons / Neurobiology / Neurology / Neurosciences / Original / Original Article / Overexpression / Protein Transport / Regulatory sequences / Spinal cord / Translation