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

Abstract

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, frontotemporal 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 effects on FUS pathology. We performed whole-exome sequencing on a 50-year-old FTLD patient with ubiquitin and FUS-positive neuronal inclusions and unaffected parents, and identified 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, suggesting that this mutation leads to NCDN haploinsufficiency. We examined the effects of NCDN haploinsufficiency on FUS and found that depleting primary cortical neurons of NCDN causes a reduction in the total number of FUS-positive cytoplasmic granules. Moreover, we found that these granules were significantly larger and more highly enriched with FUS. We then examined the effects 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 identifies 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.

Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease

“…ALS and FTD-linked FUS mutations result in pathological aggregation of FUS, with varying levels of ubiquitination, in the cytoplasm and nucleus of neurons and glia throughout the affected regions of the cortex, brainstem and spinal cord (Kwiatkowski et al, 2009 ; Munoz et al, 2009 ; Vance et al, 2009 ; Suzuki et al, 2012 ). In contrast, most FTLD cases with FUS pathology (FTLD-FUS) show no evidence of mutations in the FUS gene (Seelaar et al, 2010 ; Nicolas et al, 2022 ). These cases usually present as bvFTD or FTD-MND and tend to effect younger individuals having more rapid disease progress (Perry et al, 2017 ).…”