Abstract
A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we show using patient stem cell-derived motor neurons that the repeat expansion impairs microtubule-based transport, a process critical for neuronal survival. 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. Both arginine-rich DPRs similarly inhibit axonal trafficking in adult Drosophila neurons in vivo. Physical interaction studies demonstrate that arginine-rich DPRs associate with motor complexes and the unstructured tubulin tails of microtubules. Single-molecule imaging reveals that microtubule-bound arginine-rich DPRs directly impede translocation of purified dynein and kinesin-1 motor complexes. 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.
Highlights
Amyotrophic 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]
We show that exposure to poly-PR and poly-GR elicits comparable effects in control induced pluripotent stem cells (iPSCs)-derived motor neurons and Drosophila neurons within the intact animal
To investigate whether C9-ALS/FTD is associated with impaired microtubule-based transport, we first generated spinal motor neurons from fibroblast-derived iPSC lines from four C9orf72 patients and three healthy controls
Summary
Amyotrophic 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]. Of the several other genes that have been associated with ALS [29], three encode proteins important for microtubule-based cargo transport: the tubulin isotype 4a [30], the plus end-directed kinesin-1 motor KIF5A [31], and DCTN1, a component of the dynactin complex that activates the minus end-directed motor cytoplasmic dynein-1 (hereafter dynein) [32]. The association of these mutations with ALS suggests that motor neurons, which are selectively targeted by the disease, are reliant on efficient cargo trafficking, presumably due to their extended processes. Our data strengthen the evidence that defective axonal cargo trafficking contributes to ALS pathogenesis and implicate inhibitory interactions of arginine-rich DPRs with the axonal transport machinery in C9-ALS/FTD
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