The role of ubiquitinated TDP-43 in amyotrophic lateral sclerosis

Abstract

Deposition of intracellular ubiquitin inclusion in motor neurons is one of the leading pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). The transactive response DNA binding protein-43 (TDP-43) is the main component of intracellular ubiquitin inclusion bodies in pathological deposits. TDP-43 is mainly distributed in the nucleus of neurons, and participates in nuclear RNA transcription, alternative splicing and mRNA stability regulation. The tardbp , as a coding gene, provides instructions for making TDP-43. After post-translational modification, the pathological TDP-43 induces pathological deposition in cells and is associated with neurodegenerative diseases, which is similar to tau in Alzheimer's disease and alpha-synuclein in Parkinson's disease. The pathogenic tardbp mutation can affect the localization of reverse transcription in the cell. This review summarizes the mechanisms underlying the pathogenesis of ALS by ubiquitination of TDP-43 protein.

Sequestration of TDP-43216-414 aggregates by cytoplasmic expression of the proSAAS chaperone

“…Surprisingly, co-expression of cyto-proSAAS with TDP-43 216-414 radically altered the distribution of TDP-43 aggregates, as most cells then restricted their total TDP-43 fluorescence to the core of the proSAAS spheres. TDP-43 aggregates are predominantly cleared thorough proteasomal degradation following ubiquitination (Dong and Chen, 2018;Neumann et al, 2006), and we confirmed the presence of this modification on TDP-43 aggregates entering proSAAS spheres. Although the specific segment of TDP-43 we used in our studies is known to impair its autophagy (Cicardi et al, 2018), using a fluorescent autophagy (LC3) reporter we could rule out a role for cyto-proSAAS in TDP-43 autophagy.…”

“…Using HAdirected antiserum, we found that cyto-proSAAS was not ubiquitinated, either when coexpressed with UBK48-HA alone (Figure 6A, top row) or in the added presence of TDP43 (Figure 6A, bottom row). However, TDP43 216-414 aggregates were ubiquitinated (notched arrowheads, Figure 6A, middle row), a previously reported feature of aggregated TDP43 (reviewed in (Dong and Chen, 2018)). Interestingly, when co-expressed with cyto-proSAAS in HEK cells, TDP43 216-414 aggregates apposing the spheres were highly ubiquitinated (notched arrowheads, Figure 6A, bottom row), suggesting that ubiquitinated TDP43 might potentially be favored for entry into cyto-proSAAS spheres.…”

Role of Nuclear Factor Kappa B (NF-κB) Signalling in Neurodegenerative Diseases: An Mechanistic Approach

“…The mutations of FUS and TARDBP genes have a similar function of encoding FUS whereas, the TARDBP gene encodes TDP-43 protein causing the 60 dominant missense mutation in the nucleus of neuron necessary for the synthesis of other proteins by binding to the DNA and regulating transcription [ 87 ]. In ALS, the mutation in TARDBP gene causes the aggregation of neurotoxic TDP-43 fragments protein in nucleus to axon by mutated ubiquitin 2 (UBQLN2) and cleaving of TDP-43 forming an aggregation in nerve cell, which increases the inflammatory responses by activation of NF-KB increasing the neuroinflammation leading to oxidative stress causing excitotoxicity in motor neurons [ 91 ]. Furthermore, the NF-KB expression seems to be elevated in the ALS during the damaging of the motor neurons in the spinal cord migrating immune cells i.e ., astrocytes and microglial [ 92 ].…”

The emerging TDP-43 proteinopathy

“…In conclusion, mechanisms of TDP-43 abnormal accumulation and toxicity, extensively reviewed by Dong and Chen [6] in addition to measurement of CSF TDP-43 levels as a diagnostic tool, are currently hot topics relevant to the majority of ALS and roughly half of FTLD patients. None.…”

“…In an elegant study, Dong and Chen [6] extensively reviewed the pathogenetic mechanisms of ubiquitinated TDP-43 in ALS, including abnormal aggregation with pathologic accumulation (oligo-and finally polymerization), redistribution from the nucleus to the cytoplasm, reduced clearance by autophagy and/or the ubiquitine-proteasome system, neurotoxicity and/or loss of function, complex interactions with other proteins and RNA affecting their function and prion-like behavior and spreading. Such an understanding of TDP-43 and its role in the mechanisms of the resulting proteinopathy, may prove to be important in two aspects, diagnosis and treatment.…”