The second is an RNA gain-of-function mechanism caused by the accumulation of expanded repeat transcripts that sequester numerous RNA-binding proteins. The first is a loss-of-function scenario due to decreased expression of C9orf72 mRNA and protein observed in C9-ALS/FTD patients.
Three non-mutually exclusive pathological mechanisms have been proposed for the hexanucleotide repeat expansions (HREs) ( 5). A GGGGCC (G 4C 2) repeat expansion in the 5′ noncoding region of the C9orf72 gene is the most common genetic cause of both ALS and FTD ( C9-ALS/FTD) ( 3, 4). In recent years, it has become evident that ALS and FTD belong to a spectrum of disorders, sharing some clinical, neuropathological, and genetic features ( 1, 2). ALS patients present with progressive muscle weakness and wasting, whereas FTD patients present with behavioral and/or language abnormalities ( 1, 2). Collectively, our study implicates inhibitory interactions of arginine-rich DPRs with axonal transport machinery in C9orf72-associated ALS/FTD and thereby points to potential therapeutic strategies.Īmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are adult-onset neurodegenerative diseases that are characterized by the degeneration of motor neurons in the spinal cord, brainstem and motor cortex, and neurons in the frontal and anterior temporal cortex, respectively ( 1, 2).
Single-molecule imaging reveals that microtubule-bound arginine-rich DPRs directly impede translocation of purified dynein and kinesin-1 motor complexes. Physical interaction studies demonstrate that arginine-rich DPRs associate with motor complexes and the unstructured tubulin tails of microtubules. Both arginine-rich DPRs similarly inhibit axonal trafficking in adult Drosophila neurons in vivo.
Cargo transport defects are recapitulated by treating neurons from healthy individuals with proline-arginine and glycine-arginine dipeptide repeats (DPRs) produced from the repeat expansion. Here, we show using patient stem cell–derived motor neurons that the repeat expansion impairs microtubule-based transport, a process critical for neuronal survival. How this mutation leads to these neurodegenerative diseases remains unclear. Bullock, and Philip Van Damme Show FewerĪ hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Gitler, Philipp Koch, Pieter Vanden Berghe, Dietmar Rudolf Thal, Catherine Verfaillie, Siddharthan Chandran, Ludo Van Den Bosch, Simon L. Selvaraj, Tijs Vandoorne, Vanesa Madan, Marka van Blitterswijk, Denitza Raitcheva, Alexander McCampbell, Koen Poesen, Aaron D. Mehta, Ann Swijsen, Raheem Fazal, … Show All …, Wenting Guo, Matthieu Moisse, Jimmy Beckers, Lieselot Dedeene, Bhuvaneish T. Young, Steven Boeynaems, Mathias De Decker, Arpan R.