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Page 4 of 10 Dong et al. Neuroimmunol Neuroinflammation 2018;5:5 I http://dx.doi.org/10.20517/2347-8659.2017.47

frontotemporal dementia (FTD). In addition, the pathogenic mutations caused by tardbp are concentrated
in the glycine enriched region of the C terminus [23,26] . So far, over 60 mutations in tardbp have been found to
[24]
cause fALS and FTD ; they are listed in Table 1 as extracted from the ClinVar database. Tardbp mutations
[11]
in the nucleus might disrupt the formation of alpha helices, or their ability to stabilize . Mutations in
the spiral region affect molecular binding, concentration and the separation phase. The aggregation of
pathological TDP-43 is due to the overexpression and stacking of TDP-43 proteins. The TDP-43 prion-
like domain appears to have an energy landscape, which allows the assembly of the wild-type sequence
into dynamic oligomers only under very limited conditions. ALS-causing point mutations are sufficient to
remodel it into a more favorable formation of amyloid and its irreversible aggregation, thus supporting the
emerging view that such pathologic aggregation may occur via the exaggeration of functionally important
[24]
assemblies .
[11]
TDP-43 oligomers may further delay the release from each other , resulting in the TDP-43 oligomerization
[24]
in the nucleus, which is a possible mechanism of disruption of TDP-43 . Aging or inhibition of protein
degradation may increase the toxicity of TDP-43 in glial cells and cause neuropathological changes.

TDP-43 C-terminus encodes a prion-like domain, widely presented in RNA-binding proteins like a prion-
like domain. C-terminus is essential for solubility and cellular localization, because its deletion results in
the formation of large nuclear and cytoplasmic aggregates . Disruption of the RNA-recognition domain
[14]
required for RNA and DNA binding, however, alters nuclear distribution by decreasing TDP-43 presence in
the nucleoplasm.

The assembly of the wild-type sequence into dynamic oligomers was only seen under very limited
conditions; ALS-causing point mutations are sufficient to remodel it to favor the amyloid formation or
irreversible aggregation, thus supporting the emerging view that pathologic aggregation may occur via
[24]
the exaggeration of functionally important assemblies . Furthermore, the coupled capacity of TDP-43 in
aggregation and membrane interaction may critically account for its high neurotoxicity .
[27]
In addition, the proteinopathy of D169G and K263E mutants at the RRM domain of TDP-43 could form
the basis of ALS, including the increased solvent-accessible surface area, conformational flexibility as well
as unfolding of TDP-43, and the altered RNA conformation in TDP-43-RNA complex. These changes also
[28]
brought the enhanced aggregation propensity in the cytoplasm . These novel findings were important to
illustrate the mechanism in the structural and functional aspects of ALS development.

REDISTRIBUTION OF INTRACELLULAR TDP-43
[6]
The abnormal TDP-43 fragments would be re-distributed in the extracellular region of the nucleus . More
studies suggested that TDP-43 solubility and localization are particularly sensitive to disruptions that
extend beyond the newly found nuclear localization signal and depend on a combination of factors that
are closely connected to the functional properties of this protein . TDP-43 fragmentation accelerates the
[14]
formation of inclusion body and cell mRNA processing. The N-terminus fragment is highly distinctive,
[6]
which promotes aggregation of the C-terminus structure . When overexpression of TDP-43 and its C-
terminal fragments in HEK293T cells, fragments of TDP-43 protein and TDP35 are recruited and removed
into the cytoplasmic inclusion bodies . TDP-35 participates in the aggregation of mRNA precursors,
[8]
which makes the transformation of proteins into polymers easier. The insoluble fraction of ALS acts as a
seed of TDP-43 aggregation when it is introduced in SH-SY5Y cells, and subsequently transmitted to other
co-cultured cells [19,29] . Such extracellular accumulation, in a potentially more harmful way, is similar to
the prion infections [30,31] . In addition, normal TDP-43 distribution in nucleus is not toxic to the cell, while
[3]
only tardbp mutants cause redistribution in the extracellular region of the nucleus with neurotoxicity .
In a clinical study, previous work showed that accumulation of pathological TDP-43 or FUS coexist with