{Reference Type}: Journal Article
{Title}: Identifying FUS amyotrophic lateral sclerosis disease signatures in patient dermal fibroblasts.
{Author}: Kumbier K;Roth M;Li Z;Lazzari-Dean J;Waters C;Hammerlindl S;Rinaldi C;Huang P;Korobeynikov VA; ;Phatnani H;Shneider N;Jacobson MP;Wu LF;Altschuler SJ;
{Journal}: Dev Cell
{Volume}: 59
{Issue}: 16
{Year}: 2024 Aug 19
{Factor}: 13.417
{DOI}: 10.1016/j.devcel.2024.05.011
{Abstract}: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, highly heterogeneous neurodegenerative disease, underscoring the importance of obtaining information to personalize clinical decisions quickly after diagnosis. Here, we investigated whether ALS-relevant signatures can be detected directly from biopsied patient fibroblasts. We profiled familial ALS (fALS) fibroblasts, representing a range of mutations in the fused in sarcoma (FUS) gene and ages of onset. To differentiate FUS fALS and healthy control fibroblasts, machine-learning classifiers were trained separately on high-content imaging and transcriptional profiles. "Molecular ALS phenotype" scores, derived from these classifiers, captured a spectrum from disease to health. Interestingly, these scores negatively correlated with age of onset, identified several pre-symptomatic individuals and sporadic ALS (sALS) patients with FUS-like fibroblasts, and quantified "movement" of FUS fALS and "FUS-like" sALS toward health upon FUS ASO treatment. Taken together, these findings provide evidence that non-neuronal patient fibroblasts can be used for rapid, personalized assessment in ALS.