A PR plug for the nuclear pore in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and uniformly fatal neurodegenerative disease characterized by loss of motor neurons in the brain and spinal cord (1). ALS overlaps clinically and genetically with other adult-onset neurodegenerative disorders, most often frontotemporal dementia (FTD), suggesting that the disease may represent one manifestation of a broader clinical spectrum. Mounting evidence suggests that impairment of nucleocytoplasmic transport contributes to the most common genetic form of ALS and FTD, although the underlying mechanism has remained obscure. In PNAS, a study by Shi et al. (2) provides evidence that toxic disease-related peptides directly obstruct the central channel of the nuclear pore complex. Fittingly, this study appears on the 50th anniversary of Gall’s seminal electron microscopy study (3) that revealed the architecture of the nuclear pore. ALS usually presents sporadically, with no clear family history of motor neuron disease. Nevertheless, substantial evidence points to a strong genetic component to the disease. About 10% of cases of ALS are transmitted within families, almost always as dominant traits, and frequently with high penetrance (4). Recently, the most frequent genetic cause of both ALS and FTD was determined to be microsatellite expansion in the gene C9ORF72 (5, 6). The offending mutation is an expansion of an intronic hexanucleotide repeat, GGGGCC (G4C2). Unaffected individuals typically have between two and 23 G4C2 repeats, whereas people with C9ORF72 -related ALS and FTD (hereafter referred to as C9-ALS/FTD) have hundreds or even thousands of repeats. This mutation is very common, accounting for up to 40% of familial cases and ∼5–10% of sporadic cases of ALS-FTD (4). The primary driver of disease downstream of G4C2 repeat expansion appears to be toxic gain of function arising from repeat-containing transcripts of C9ORF72 … [↵][1]1Email: jpaul.taylor{at}stjude.org. [1]: #xref-corresp-1-1