Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis
1 Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA and 2 Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
* To whom correspondence should be addressed at: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, 3600 Spruce Street, 3rd Floor Maloney Building, Philadelphia, PA 19104, USA. Tel: +1 2156626427; Fax: +1 2153495909; E-mail: trojanow{at}mail.med.upenn.edu
Received June 22, 2009; Revised June 22, 2009; Accepted June 30, 2009
Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease that affects 
2/100 000 individuals each year worldwide. Patients with ALS suffer from rapidly progressive degeneration of motor neurons ultimately leading to death. The major pathological features observed in post-mortem tissue from patients with ALS are motor neuron loss, cortical spinal tract degeneration, gliosis and cytoplasmic neuronal inclusions formed by TDP-43 or TAR DNA binding Protein with a molecular mass of 43 kDa, which are now recognized as the signature lesions of sporadic ALS. TDP-43 possesses two RNA binding domains (RBD) and a glycine-rich C terminus classifying it with other heterogeneous nuclear ribonucleoproteins known as 2XRBD-Gly proteins. A number of reports showed that a subset of patients with ALS possess mutations in the TDP-43 (TARDBP) gene. This further strengthens the hypotheses that gain of toxic function or loss of function in TDP-43 causes ALS. Currently, 29 different TARDBP missense mutations have been reported in 51 unrelated sporadic or familial ALS cases and two cases of ALS plus concomitant frontotemporal lobar degeneration with a remarkable concentration of mutations in the C-terminal glycine-rich domain of TDP-43. As these mutations will most certainly be an invaluable tool for the design and implementation of ALS animal and cell models, as well as serve as a platform for exploring the pathobiology of TDP-43, here we summarize the identified pathogenic TARDBP mutations and their potential impact on our understanding of the role of TDP-43 in disease.