Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease that affects approximately 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.

Figure 1.

The glycine-rich domain protein sequence alignment of TDP-43 and hnRNP-A1 is shown with amino acid numbering (top) corresponding to the TDP-43 amino acid number. Identical and similar amino acid residues are boxed and colored in orange and grey, respectively. Glycines are highlighted in red and the arrows indicate missense mutations in TDP-43 with their corresponding amino acid change.

Figure 2.

Immunohistochemical staining of TDP-43 in spinal cord motor neurons from control subject (left), a sporadic ALS patient (middle) and a fALS patient harboring the G298S mutation (right) illustrate that TDP-43 pathology in ALS cases with and without a TARDBP missense mutation is indistinguishable.