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Knowledge about converging disease mechanisms in the heterogeneous syndrome amyotrophic lateral sclerosis (ALS) is rare, but may lead to therapies effective in most ALS cases. Previously, we identified serum microRNAs downregulated in familial ALS, the majority of sporadic ALS patients, but also in presymptomatic mutation carriers. A 5-nucleotide sequence motif (GDCGG; D = G, A or U) was strongly enriched in these ALS-related microRNAs. We hypothesized that deregulation of protein(s) binding predominantly to this consensus motif was responsible for the ALS-linked microRNA fingerprint. Using microRNA pull-down assays combined with mass spectrometry followed by extensive biochemical validation, all members of the fragile X protein family, FMR1, FXR1 and FXR2, were identified to directly and predominantly interact with GDCGG microRNAs through their structurally disordered RGG/RG domains. Preferential association of this protein family with ALS-related microRNAs was confirmed by in vitro binding studies on a transcriptome-wide scale. Immunohistochemistry of lumbar spinal cord revealed aberrant expression level and aggregation of FXR1 and FXR2 in C9orf72- and FUS-linked familial ALS, but also patients with sporadic ALS. Further analysis of ALS autopsies and induced pluripotent stem cell-derived motor neurons with FUS mutations showed co-aggregation of FXR1 with FUS. Hence, our translational approach was able to take advantage of blood microRNAs to reveal CNS pathology, and suggests an involvement of the fragile X-related proteins in familial and sporadic ALS already at a presymptomatic stage. The findings may uncover disease mechanisms relevant to many patients with ALS. They furthermore underscore the systemic, extra-CNS aspect of ALS., Freischmidt et al. show direct interaction of fragile X proteins with a subset of microRNAs that share a common sequence motif and that are downregulated in the majority of patients with ALS. Neuropathology suggests contribution of the fragile X proteins to a convergent disease mechanism implicated in many cases of ALS.

Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.

Sir, Bannwarth et al. (2014) reported a mutation in CHCHD10 responsible for a variable phenotype including cerebellar ataxia, hearing impairment, myopathy, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This gene encodes the coiled-coil helix coiled-coil helix domain-containing protein 10 of largely unknown function. It is a strictly mitochondrially located protein that may be involved in respiratory chain function or mitochondrial genome stability (Bannwarth et al. , 2014). Several subsequent publications provided further evidence that CHCHD10 mutations can cause familial motor neuron disease/ALS (familial ALS), with an unusually slow disease progression in most patients (Bannwarth et al. , 2014; Johnson et al. , 2014; Muller et al. , 2014; Kurzwelly et al. , 2015; Penttila et al. , 2015). As an important argument for CHCHD10 causing ALS, co-segregation with disease could be demonstrated for the three CHCHD10 variants p.R15L (Johnson et al. , 2014; Muller et al. , 2014; Kurzwelly et al. , 2015), p.S59L (Bannwarth et al. , 2014) and p.G66V (Penttila et al. , 2015). The strongest genetic evidence for causality exists with regard to the p.G66V mutation, which was first detected by Muller et al. (2014) in a single patient with familial ALS and subsequently shown to co-segregate with a slowly progressing motor neuron disease in a total of 17 pedigrees (Penttila et al. , 2015). Hence there is meanwhile unequivocal evidence that CHCHD10 mutation can cause familial motor neuron degeneration. No association of CHCHD10 variants with ALS could be shown in genome-wide association studies, which can plausibly be explained by the low frequency of CHCHD10 mutations in familial ALS patient cohorts (Bannwarth et al. , 2014; Johnson et al. , 2014; Muller et al. , 2014). Consequently, due to the …