Poly-A Binding Protein-1 Localization to a Subset of TDP-43 Inclusions in Amyotrophic Lateral Sclerosis Occurs More Frequently in Patients Harboring an Expansion inC9orf72

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease in which the loss of spinal cord motor neurons leads to paralysis and death within a few years of clinical disease onset. In almost all cases of ALS, TAR DNA binding protein of 43 kDa (TDP-43) forms cytoplasmic neuronal inclusions. A second causative gene for a subset of ALS is fused in sarcoma (FUS), an RNA binding protein that also forms cytoplasmic inclusions in spinal cord motor neurons. Poly A binding protein 1 (PABP-1) is a marker of stress granules, i.e. accumulations of proteins and RNA indicative of translational arrest in cells under stress. We report on the colocalization PABP-1 to both TDP-43 and FUS inclusions in 4 patient cohorts: ALS without a mutation, ALS with an intermediate poly glutamine repeat expansion in ATXN2, ALS with a GGGGCC-hexanucleotide repeat expansion in C9orf72, and ALS with basophilic inclusion body disease. Notably, PABP-1 colocalization to TDP-43 was twice as frequent in ALS with C9orf72 expansions compared to ALS with no mutation. This study highlights PABP-1 as a protein important to the pathology of ALS and indicates that the proteomic profile of TDP-43 inclusions in ALS may be different depending on the causative genetic mutation.

The Role of TDP-43 in Alzheimer’s Disease

“…PPIA regulates expression of known TDP-43 RNA targets and is necessary for the assembly of TARDBP in hnRNP complexes [14]. Several other genes, including progranulin (PGRN), valosin-containing protein (VCP), and C9ORF72, are also reported to relate to TDP-43 proteinopathies [15][16][17][18].…”

TDP-43/FUS in motor neuron disease: Complexity and challenges

“…Like TDP-43, RBM-45 is mainly nuclear, but migrates to cytoplasm and co-localizes in SGs to associate with Kelch-like ECH-Associated protein 1, a component of anti-oxidant machinery (Bakkar et al, 2015). Furthermore, TDP-43 co-localizes in cytoplasmic inclusions with Poly-A binding protein - 1 (PABP-1); a stress granules marker (McGurk et al, 2014). …”

“…Strikingly, these patients develop numerous p62-positive, TDP-43-negative inclusions in the dentate gyrus, neocortex, and cerebellum (Al-Sarraj et al, 2011; Boxer et al, 2011; DeJesus-Hernandez et al, 2011). Furthermore, patients with the C9orf72 hexanucleotide expansion also have RBM45 inclusions and PABP-1 (Collins et al, 2012; McGurk et al, 2014). C9orf72 mutations appear to promote mis-localization of TDP-43 to the cytoplasm, in addition to causing malformed RNA molecules (Zhang et al, 2015).…”

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

“…Deletion of the RNA-binding domains in TDP43 and FUS both prevents their inclusion in stress granules and reduces their toxicity [34,[39][40][41]. Moreover, components of stress granules have been detected in TDP43-rich cytoplasmic deposits in spinal neurons of patients with ALS [56,99,101], but are less common in cortical neurons [102]. These results may be explained by the preferential accumulation of fulllength TDP43 in spinal neurons of patients with ALS, in contrast to the deposition of carboxy-terminal fragments of TDP43 in cortical neurons [103].…”