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Dong et al. Neuroimmunol Neuroinflammation 2018;5:5 I http://dx.doi.org/10.20517/2347-8659.2017.47 Page 3 of 10

in contrast to this inhibition. On the other hand, TDP 43 was also found to repress cryptic exon splicing
[14]
in order to promote cell survival . TDP-43-dependent splicing defects, revealing TDP-43 extensively
regulated cryptic splicing, are a significant overlap in genes that undergo TDP-43-dependent cryptic splicing
[14]
repression .

THE ORIGIN OF PATHOLOGICAL TDP-43
Pathological TDP-43 mediated neuronal death is mainly caused by neurotoxicity and loss of TDP-43
[17]
function . Phosphorylation and ubiquitination of TDP-43, the major features of pathological TDP-43,
have not been detected in the normal brain. Phosphorylated and/or ubiquitinated TDP-43 have been found
[4]
in the brain and spinal cord of patients with ALS . In human studies, not all of TDP-43 inclusion bodies
have been ubiquitinated, especially in the early stage of ALS, which suggests that ubiquitination is an
[18]
advanced metabolic phenomenon in ALS disease . The phosphorylated TDP-43 exists more commonly
with serine (Ser) 379, Ser 403 + Ser 404, Ser 409 +, and Ser 410, which mainly between Ser 409-410. Most of
the inclusion bodies of TDP-43 and TDP-43 25-kDa, as the degradation fragments of TDP 43, are detected
[4]
in the phosphorylated form . Therefore, the process of phosphorylation is likely preceded by ubiquitination.
However, it is still unclear which form plays a more determinant role in mediating TDP-43 induced
neurodegeneration.

[19]
In pathological conditions, TDP-43 protein degrades into two degradation fragments at the C-terminal .
By selectively expressing mutations in neurons and glial cells, the pathological TDP-43 protein is more
commonly found to concentrate in neuronal cells, which may cause it failure to regulate synaptic plasticity
and neuronal death [8,20] . Thus, mistakenly accumulated TDP-43 in motor neurons might be the initial
[20]
mechanism of ALS onset .
The fragments of TDP-43 protein can induce TDP-43 deposition, which is related to the ubiquitin
proteasome system [5,21] . The overexpression of the full-length protein of TDP-43 and its aggregation can be
detected in high expression of tardbp CTFs cells. Although both TDP-43 and TDP-43 fragments would be
affected by the ubiquitin proteasome system, CTFs fragments are more likely to foster transcription without
stopping due to the absence of two nuclear localization signals. In addition, Cdc48TS, as an enhancer of
[22]
neurotoxicity, promotes the deposition of pathological TDP-43 . Thus, any influence on the ubiquitin
proteasome system may increase the expression of ubiquitination of TDP-43.

PATHOGENESIS OF TDP-43
In Drosophila motor neurons, the high expression of TDP-43 caused axonal swelling and impaired
[23]
mobility. Moreover, impairment was more severe in the motor neurons of A315T mutant phenotype . The
TDP-43 peptide segments can form in vitro in both the wild-type and A315T mutant, which are misfolded
[23]
like precipitation as seen using an electron microscope . Therefore, the main pathogenesis of ALS may be
caused by the abnormal accumulation of TDP-43 in motor neurons and secondary atrophy of neurons or
glial cells.

According to the findings in polymerization kinetics study, the pathological C terminus had a prion-like
domain structure. This prion domain is present in most of the pathogenic mutations of TDP-43 [23,24] . The
pathological C terminus is intrinsically disordered only with some nascent secondary structures in aqueous
solutions, but processes the capacity to assemble into dynamic oligomers rich in b-sheet structures. There
[25]
structures interact with nucleic acid, which triggers rapid aggregation for most mutants . Although RNA-
binding protein prion-like domains have no homology or sequence similarity to the human prion protein
that forms infectious protein aggregates in new variant Creutzfeldt-Jakob disease, many of these proteins
have been identified as the major components of cytoplasmic inclusions associated with subtypes of ALS and