Overexpression of Wild-type TDP-43 Leads to Motor Neuron Degeneration and Spastic Quadriplegia in Germline Transgenic Mice

Abstract

Background: Frontotemporal dementia (FTD) is a clinical syndrome with heterogeneous molecular basis. Although the neuropathology associated with most FTD is characterized by abnormal cellular aggregates of either TDP-43 or tau protein, there remains a significant subgroup (w15%) characterized by ubiquitin-immunoreactive (ub-ir) inclusions that are negative for both tau and TDP-43. Missense mutations in the gene encoding the fused in sarcoma (FUS) protein (also known as translated in liposarcoma, TLS), on chromosome 16, have recently been identified as a cause of familial amyotrophic lateral sclerosis (ALS). The associated pathology is described as including neuronal inclusion bodies that are immunoreactive for FUS (FUS-ir) but negative for TDP-43. Objective: Because of the recognized clinical, genetic and pathological overlap between ALS and FTD, we investigated the possible role of FUS in FTD. Methods: Immunohistochemistry, double label immunofluorescence, immunoblotting, and molecular genetic analysis. Results: In all cases, FUS immunohistochemistry (IHC) demonstrated normal physiological staining of neuronal nuclei and cytoplasm and some glial nuclei. No FUS-ir pathology was identified in cases of FTD with TDP-43 or tau pathology, or TDP-43-positive ALS. However, in a significant proportion of cases with tau/TDP-43-negative FTD, FUS IHC labeled neuronal cytoplasmic and intranuclear inclusions of similar morphology, number and anatomical distribution as were demonstrated with ubiquitin IHC. The co-localization of FUS and ubiquitin in neuronal inclusions was confirmed with double label immunofluorescence. Neurons that contained inclusions retained at least some normal physiological FUS staining. FUS IHC also demonstrated previously unrecognized inclusions in glial cells. The pathological changes were demonstrated with multiple antibodies that recognize different epitopes across the entire FUS protein. Immunoblot analysis confirmed increased amounts of insoluble FUS in post-mortem brain tissue from these cases. All cases of FTD with FUS pathology were sporadic and molecular genetic analysis did not identify any mutations in the FUS gene or abnormal levels of FUS mRNA expression. Conclusion: These findings suggest that FUS is the pathological protein in a significant subgroup of sporadic FTD and reinforce the concept that FTD and ALS are closely related conditions.