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

Abstract

Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.

TDP-43 facilitates milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh

“…To date, however, few studies have attempted to identify upstream regulatory factors of XOR and BTN. Encoded by the Tardbp gene, TDP-43 is well recognized as an essential factor in amyotrophic lateral sclerosis and frontotemporal lobar degeneration 55,56 . Previous studies have shown that TDP-43 is involved in the progression of breast and other cancers 29,57,58 .…”

Neuronal cytoplasmic inclusions in tau, TDP-43, and FUS molecular subtypes of frontotemporal lobar degeneration share similar spatial patterns

“…Compared with tau, which is widespread in neurons and important in the assembly and stabilisation of microtubules [27,51], both TDP-43 and FUS have more specific roles, TDP-43 in mRNA function, DNA repair, and in non-coding RNA metabolism [45] while FUS is important in regulating gene expression including transcription, splicing, and RNA transport [31]. In both TDP-43 and FUS, nuclear clearance results in the immediate aggregation in the cytoplasm of cells [33]. In addition, TDP-43 can also repress non-conserved cryptic axons, many of which are cell type specific, and therefore loss of TDP-43 function could result in the degeneration of specific groups of cells [38,39].…”

Autophagy-Lysosome Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

“…Like TARDBP, mutations in FUS have been linked more closely to ALS, though positive protein aggregates for FUS appear in both ALS and FTLD [9]. FUS-positive inclusions account for about 5-10% of FTLD cases [9] and 1% of ALS cases [15]. Several proposed mechanisms link FUS to disruption of the autophagy-lysosome pathway.…”

“…Each disease is also subdivided by molecular pathology depending on the primary components of inclusion bodies, such as Tau, TDP-43 (TAR DNA-Binding Protein 43), FUS (fused in sarcoma), SOD1 (superoxide dismutase 1 ) and C9 or f72 dipeptide repeats (DPRs) [9,15]. In 2006, both ALS and FTLD were found to have neuronal inclusions composed largely of TDP-43, an RNA-binding protein, that are also ubiquitin and p62-positive, suggesting that these aggregates were tagged for degradation [16][17][18].…”