Motor neuron disease (MND) is a neurodegenerative disorder involving the loss of upper and/or lower motor neurons, and it is characterized clinically by progressive weakness and death within a few years of onset; the most common clinical MND phenotype is amyotrophic lateral sclerosis (ALS). Recently, TAR DNA-binding protein 43 (TDP-43) was identified as the major pathological protein of the motor neuron inclusions found in sporadic MND and also in frontotemporal lobar degeneration with ubiquitin-immunoreactive, tau-negative inclusions (FTLD-U), which can be associated with MND, but not in familial MND with Cu/Zn superoxide dismutase-1 (SOD1)
Although largely sporadic, about 10% of MND cases are familial, and of these about 20% have mutations in the SOD1
Evidence suggests that SOD1
mutations cause MND by a toxic gain of function.6
The recent discovery that pathological TDP-43 inclusions are present in sporadic/non-SOD1
cases of MND, but absent from SOD1
cases and SOD1
transgenic mice, suggests that the sporadic form of the disease may have a different underlying pathophysiology. Therefore, new genetic insights into MND are needed to further the understanding of disease pathogenesis and to develop animal models representative of the sporadic form of the disease.
Familial forms of neurodegenerative diseases can carry pathogenic mutations in the genes encoding the proteins present in the inclusions characterizing the disorder, for example, amyloid precursor protein in Alzheimer's disease,7
α-synuclein in Parkinson's disease,8
and tau in FTLD with tauopathy.9
Given that TDP-43-positive inclusions are present in most cases of sporadic and familial ALS, FTLD-MND, and FTLD-U, this gene is a strong biological candidate gene for familial forms of these disorders.
TDP-43 protein structure is evolutionarily conserved and consists of two RNA recognition motifs and a glycine-rich domain10
(). TDP-43 can bind DNA and RNA, is involved in exon skipping of cystic fibrosis transmembrane conductance regulator (CFTR) gene, and binds to human immunodeficiency virus type 1 TAR DNA sequence motifs.11-13
Fig TDP-43 missense mutation A315T within a highly conserved region of exon 6 segregates with all affected members of an autosomal dominant motor neuron disease (MND) family. (A) TAR DNA-binding protein 43 (TDP-43) genomic structure, position of missense (more ...)