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discovery of tdp43 mutation. In 2008, one observational study in France showed that 4% of familial ALS
[2]
patients had a tdp43 mutation . It was also found in sporadic ALS patients, which bolstered knowledge of
[2]
the pathological mechanism of ALS . The abnormal intracellular ubiquitin inclusion was confirmed to be
[3,5]
the cause of neuronal cell death . Therefore, the highly ubiquitinated phosphorylated TDP-43 protein is
closely related to the development of ALS. This review illustrates the development of TDP-43 in ALS and its
underlying mechanism.

NORMAL TDP-43 AND ITS FUNCTION
Normal TDP-43 is a protein with a length of 414 amino acids. It contains 2 RNA identity motifs (RRM1 and
[7]
[6,7]
RRM2, respectively) at the N terminal and hydrophobic sequence in the C-terminus . The presence of
the RRMs is a distinguishing feature of heterogeneous nuclear ribonucleoprotein proteins （hnRNP) and,
in general, these regions are known to mediate RNA recognition as well as protein-protein interactions. The
[8]
first RRM (RRM-1) is necessary and sufficient to bind specific RNA or DNA sequences . TDP-43 is encoded
by tardbp which mainly distributed in the nucleus. Normal TDP-43 does not form inclusion bodies and
is mainly involved in nuclear RNA transcription, mRNA precursor shear and mRNA stability regulation.
Recruitment of full-length TDP-43 into cytoplasmic deposition formed inclusion bodies. Next, TDP-43
combines with RNA/DNA and regulates RNA metabolism at multiple levels, including transcription, RNA
splicing, and mRNA stability. In TDP-43 knockout HeLa cells and HEK293 cell cultures, tdp43 can regulate
add2 gene expression by increasing Add2 mRNA stability, which is closely related to synaptic aggregation,
[7,9]
synaptic remodeling and stability . UTRs at the 3’ terminal of TDP-43 protein is a specific mRNAs that is
associated with its distribution and aggregation in cells. TDP-43 takes charge of bidirectional transcription
between the nucleus and cytoplasm. Its solubility and localization are closely related to its nuclear
[8]
localization signal. In addition, it also affects the function of the protein .
By monitoring the levels of TDP-43 oligomers in vitro, TDP-43 has been found to communicate through the
[10]
axon in the cell by synaptic and microencapsulated uptake . With the help of nuclear magnetic resonance,
simulation and microscopy, a sub-region has been found cooperatively but transiently to be folded into an
[11]
a-Helical form that mediates TDP-43 phase separation . It has also been illustrated that the low-complexity
of TDP-43 in liquid-liquid and phase-separated in vitro granules demonstrates ALS-associated variants
[11]
that disrupts interactions within the granules . It is stabilized by extending its helices-structure and
[11]
promotes binding between the molecules . Stable helical conformation was adopted by residues Pro320-
Leu340 in an isolated peptide of Met311-Gln360, while it is indeed lacking of any stable secondary structure.
An observation at the glycine rich region of C-terminal domain is relatively conservative and related to
[12]
the concentration and separation of molecules . The concentration of TDP-43 molecules depends on its
[11]
a-Helical structure of the protein C-terminal fractures (CTF) .
TDP-43 belongs to the family of the hnRNPs and is highly conserved among metazoans in both sequence
[12]
and function . In human cells, overexpression of TDP-43 decreases exon 9 recognition and specifically
[13]
causes exon skipping in vitro .
In relation to its function, TDP-43 has a variety of diverse roles including gene transcription, RNA
[14]
splicing, RNA shuttling and translation, and microRNA biogenesis . TDP-43 regulates various processes
of transcription through RNA and DNA binding. Moreover, recent reports have shown that the protein
[15]
interacts with the 3-UTRs of specific mRNAs . In a previous study, the depletion of TDP-43 through
RNA interference removes splicing inhibition caused by unfavorable (UG)mU(n) sequences, indicating that
[15]
TDP-43 exerts a potent inhibitory effect in vivo . More recently, new evidence that TDP-43 protein
continuously shuttles between the nucleus and cytoplasm in a transcription-dependent manner has been
[16]
reported . The functional TDP-43 plays a dominant role in exon 9 splicing regulatory elements and
shows that TDP-43 related splice site has determined the evolution of positive splicing regulatory elements