Most notably, TDP-43-expressing neuronal inclusions and C9orf72 mutations have emerged as the key pathological and genetic hallmarks, respectively, of ALS.
These studies uncover a hitherto unknown role of alternative TDP43 splice isoforms in ALS, and indicate that sTDP43 production may be a key contributor to the susceptibility of motor neurons in ALS.
Microglial NLRP3 upregulation was also observed in the TDP-43<sup>Q331K</sup> ALS mouse model, and TDP-43 wild-type and mutant proteins could also activate microglial inflammasomes in a NLRP3-dependent manner.
Prominent examples are amyloid beta and tau in Alzheimer's disease, α-synuclein in Parkinson's disease and transactive response DNA binding protein 43 kDa (TDP-43) in ALS and FTD.
Because phosphorylated (p) TDP-43 has been identified as a component of ubiquitin-positive and tau-negative inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), it is considered to play a major role in neurodegenerative processes.
The RNA-binding proteins TDP-43 and FUS are tied as the third leading known genetic cause for amyotrophic lateral sclerosis (ALS), and TDP-43 proteopathies are found in nearly all ALS patients.
ALS with selective involvement of the PNL and motor systems exhibits unique clinicopathological features and TDP-43 propagation routes, thus representing a distinct subtype of ALS.ANN NEUROL 2019.
Indeed, a growing number of FTD and/or ALS related RBPs coding genes (TDP43, FUS, EWSR1, TAF15, hnRNPA1, hnRNPA2B1, ATXN2, TIA1) have been identified to interfere with SG formation through mutation of their low-complexity domain (LCD), and thereby cause or influence disease.
Together with our observation that ATG7 is reduced in ALS-FTD brain tissues, these findings identify the autophagy pathway as one key effector of nuclear depletion of TARDBP that contributes to neurodegeneration.
In addition, those pathological neurofilament accumulations are known in α-synuclein in Parkinson's disease (PD), Aβ and tau in Alzheimer's disease (AD), polyglutamine in CAG trinucleotide repeat disorders, superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP43), neuronal FUS proteins, optineurin (OPTN), ubiquilin 2 (UBQLN2), and dipeptide repeat protein (DRP) in amyotrophic lateral sclerosis (ALS).
Here, we identified that Cdc48 and Ubx3, a Cdc48 co-factor implicated in endocytic function, regulates the turnover and toxicity of TDP-43 and FUS expressed in <i>S. cerevisiae</i> Cdc48 physically interacts and co-localizes with TDP-43, as does VCP in ALS patient tissue.
TAR-DNA binding protein 43 (TDP-43) is a multifunctional RNA binding protein directly implicated in the etiology of amyotrophic lateral sclerosis (ALS).
The results of the current study highlight the importance of phosphorylation and regulation of TDP-43 nuclear-cytoplasmic shuttling/redistribution, in relation to the pathogenetic mechanisms involved in different forms of ALS.
These findings are consistent with emerging studies implicating distinct pathomechanisms in the generation of pathologic TDP-43 in cases with ALS with <i>C9ORF72</i> or <i>ATXN2</i> expansions and are of relevance to therapeutic research aimed at reducing pathologic TDP-43 in all or a subset of patients with ALS.
Thus, premature polyadenylation-mediated reduction in stathmin-2 is a hallmark of ALS-FTD that functionally links reduced nuclear TDP-43 function to enhanced neuronal vulnerability.
Even though the aggregative property of TDP-43 is considered a cornerstone of amyotrophic lateral sclerosis, there has been major controversy regarding the functional link between TDP-43 aggregates and cell death.
We considered the present case to be an example of lower motor neuron-predominant ALS. p-TDP-43-immunoreactive aggregates in neurons, but not in glial cells, may be an early-stage pathology of ALS.
We further demonstrate that transient SG formation contributes to persistent accumulation of TDP-43 into cytoplasmic puncta and that our hit compounds can reduce this accumulation in iPS-MNs from ALS patients.
TAR DNA-binding protein 43 (TDP-43) is the major component of the ubiquitin-positive protein aggregates seen in the majority of frontotemporal lobar degeneration and amyotrophic lateral sclerosis cases.
Moreover, modulation of TDP-43 by an in-house designed protein casein kinase-1δ (CK-1δ) inhibitor, IGS3.27, reduced phosphorylation of TDP-43, and normalized the nucleo-cytosol translocation of TDP-43 in ALS lymphoblasts.
Therapeutic approaches that inhibit SG formation may therefore be effective at suppressing TDP-43-mediated toxicity in patients with ALS and related TDP-43 proteinopathies.