A postzygotic de novo NCDN mutation identified in a sporadic FTLD patient results in neurochondrin haploinsufficiency and altered FUS granule dynamics

Frontotemporal dementia (FTD) is a heterogeneous clinical disorder characterized by progressive abnormalities in behavior, executive functions, personality, language and/or motricity. A neuropathological subtype of FTD, frontotem‑poral lobar degeneration (FTLD)-FET, is characterized by protein aggregates consisting of the RNA-binding protein fused in sarcoma (FUS). The cause of FTLD-FET is not well understood and there is a lack of genetic evidence to aid in the investigation of mechanisms of the disease. The goal of this study was to identify genetic variants contributing to FTLD-FET and to investigate their efects on FUS pathology. We performed whole-exome sequencing on a 50-yearold FTLD patient with ubiquitin and FUS-positive neuronal inclusions and unafected parents, and identifed a de novo postzygotic nonsense variant in the NCDN gene encoding Neurochondrin (NCDN), NM_014284.3:c.1206G>A, p.(Trp402*). The variant was associated with a~31% reduction in full-length protein levels in the patient’s brain, sug‑gesting that this mutation leads to NCDN haploinsufciency. We examined the efects of NCDN haploinsufciency on FUS and found that depleting primary cortical neurons of NCDN causes a reduction in the total number of FUS-posi‑tive cytoplasmic granules. Moreover, we found that these granules were signifcantly larger and more highly enriched with FUS. We then examined the efects of a loss of FUS function on NCDN in neurons and found that depleting cells of FUS leads to a decrease in NCDN protein and mRNA levels. Our study identifes the NCDN protein as a likely contributor of FTLD-FET pathophysiology. Moreover, we provide evidence for a negative feedback loop of toxicity between NCDN and FUS, where loss of NCDN alters FUS cytoplasmic dynamics, which in turn has an impact on NCDN expression