Prion diseases, or transmissible spongiform encephalopathies (TSEs), are neurodegenerative disorders that affect both humans and animals. The first TSE observed historically was scrapie, which affects both ovine (sheep) and caprine (goat) species. Subsequently, prion diseases have been observed in cattle (bovine spongiform encephalopathy; BSE or "mad cow disease"); cervids such as deer, elk and moose (chronic wasting disease; CWD); minks (transmissible mink encephalopathy), felines (feline spongiform encephalopathy) and, most recently, dromedary camels (camel prion disease) (Babelhadj et al., AbstractPrions, which cause fatal neurodegenerative disorders such as Creutzfeldt-Jakob disease, are misfolded and infectious protein aggregates. Currently, there are no treatments available to halt or even delay the progression of prion disease in the brain.The infectious nature of prions has resulted in animal paradigms that accurately recapitulate all aspects of prion disease, and these have proven to be instrumental for testing the efficacy of candidate therapeutics. Nonetheless, infection of cultured cells with prions provides a much more powerful system for identifying molecules capable of interfering with prion propagation. Certain lines of cultured cells can be chronically infected with various types of mouse prions, and these models have been used to unearth candidate anti-prion drugs that are at least partially efficacious when administered to prion-infected rodents. However, these studies have also revealed that not all types of prions are equal, and that drugs active against mouse prions are not necessarily effective against prions from other species. Despite some recent progress, the number of cellular models available for studying non-mouse prions remains limited. In particular, human prions have proven to be particularly challenging to propagate in cultured cells, which has severely hindered the discovery of drugs for Creutzfeldt-Jakob disease. In this review, we summarize the cellular models that are presently available for discovering and testing drugs capable of blocking the propagation of prions and highlight challenges that remain on the path towards developing therapies for prion disease.

The discovery of TDP-43 as a major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) was first made in 2006. Prior to 2006 there were only 11 publications related to TDP-43, now there are over 2000, indicating the importance of TDP-43 to unraveling the complex molecular mechanisms that underpin the pathogenesis of ALS/FTLD. Subsequent to this discovery, TDP-43 pathology was also found in other neurodegenerative diseases, including Alzheimer's disease, the significance of which is still in the early stages of exploration. TDP-43 is a predominantly nuclear DNA/RNA-binding protein, one of a number of RNA-binding proteins that are now known to be linked with ALS/FTLD, including Fused in Sarcoma (FUS), heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1). However, what sets TDP-43 apart is the vast number of cases in which TDP-43 pathology is present, providing a point of convergence, the understanding of which could lead to broadly applicable therapeutics. Here we will focus on TDP-43 in ALS/FTLD, its nuclear and cytoplasmic functions, and consequences should these functions go awry.

Neuronal cytoplasmic aggregation and ubiquitination of TDP-43 is the most common disease pathology linking Amyotrophic Lateral Sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 pathology is characterized by the presence of low molecular weight TDP-43 species generated through proteolytic cleavage and/or abnormal RNA processing events. In addition to N-terminally truncated TDP-43 species, it has become evident that C-terminally truncated variants generated through alternative splicing in exon 6 also contribute to the pathophysiology of ALS/FTLD. Three such variants are listed in UCSD genome browser each sharing the same C-terminal unique sequence of 18 amino acids which has been shown to contain a putative nuclear export sequence. Here we have identified an additional C-terminally truncated variant of TDP-43 in human spinal cord tissue. This variant, called TDP43C-spl, is generated through use of non-canonical splice sites in exon 6, skipping 1,020 bp and encoding a 272 aa protein lacking the C-terminus with the first 256 aa identical to full-length TDP-43 and the same 18 amino acid C-terminal unique sequence. Ectopic expression studies in cells revealed that TDP43C-spl was localized to the nucleus in astrocytic and microglial cell lines but formed cytoplasmic ubiquitinated aggregates in neuronal cell lines. An antibody raised to the unique 18 amino acid sequence showed elevated levels of C-terminally truncated variants in ALS spinal cord tissues, and co-labeled TDP-43 pathology in disease affected spinal motor neurons. The retention of this 18 amino acid sequence among several C-terminally truncated TDP-43 variants suggests important functional relevance. Our studies of TDP43C-spl suggest this may be related to the selective vulnerability of neurons to TDP-43 pathology and cell-subtype differences in nuclear export.