ALS and FTLD are two related neurodegenerative diseases 
and may fall within the same disease spectrum. While a subset of FTLD patients develop motor neuron disease 
, ALS patients may develop the symptoms and pathology of FTLD 
. FUS and TDP-43 are two ribonucleoproteins and their mutant forms are linked to both ALS and FTLD 
. We obtained two FUS transgenic lines expressing a mutant or normal human fus
transgene at comparable levels. Transgenic rats expressing a mutant FUS developed progressive paralysis secondary to axonal degeneration and displayed a substantial loss of neurons in the cortex and hippocampus, reproducing some phenotypes of ALS and FTLD. While the mutant FUS transgenic rats developed some phenotypes of ALS and FTLD, the age-matched normal FUS transgenic rats were asymptomatic. Our findings in FUS transgenic rats confirm that mutation of the fus
gene is related to these two diseases and suggest that mutation of the fus
gene is pathogenic.
FUS proteinopathy characterizes a subset of sporadic FTLD, in which ubiquitin-positive inclusions are negative for TDP-43 and tau but positive for FUS protein 
. However, it is not known how normal FUS is related to neurodegeneration in these diseases. While overexpression of mutant FUS induced severe phenotypes in young animals, overexpression of the normal FUS also induced neuron death as well as learning and memory deficits in aged rats. Mutated FUS appeared more toxic in transgenic rats, but an increase in the expression or function of the fus
gene may elicit neurotoxicity. The effects of gene mutation include gain-of-function, loss-of-function, and dominant-negative effects. Overexpression of either the mutant or wild-type FUS induced disease phenotypes in transgenic rats, suggesting that mutation of the fus
gene may cause the disease by a gain of toxic properties. Since gain-of-function and dominant-negative mutations can induce similar effects in transgenic models, more sophisticated genetic approaches, such as gene knockin, may be required for determining the nature of FUS mutations.
FUS and TDP-43 show a similarity in disease induction. Mutant forms of these genes are more toxic than the normal genes 
, and increased expression of the normal genes is sufficient to induce neurodegeneration 
. Both FUS and TDP-43 are ribonucleoproteins and may have overlapping functions. Indeed, FUS and TDP-43 are found in one protein complex regulating HDAC6 mRNA 
. Like TDP-43, FUS predominantly resides in the nucleus, but also shuttles between the nucleus and the cytoplasm to perform multiple functions 
. Similar to results for TDP-43 
, we found that FUS was diffusely located in the cytoplasm in transgenic rats. Possibly, redistribution of FUS may alter the functions of this multifunctional protein, incurring cellular toxicity.
In summary, our results suggest that mutant FUS is more toxic to neurons than normal FUS and that increased expression of normal FUS is sufficient to induce neuron death. Our FUS transgenic rats reproduced some phenotypes of ALS and FTLD. The establishment of these FUS transgenic rat lines will allow for more detailed studies of FUS-related diseases.