Structural insights into the multi-determinant aggregation of TDP-43 in motor neuron-like cells

Bozzo, Francesca; Salvatori, Illari; Iacovelli, Federico; Mirra, Alessia; Rossi, Simona; Cozzolino, Mauro; Falconi, Mattia; Valle, Cristiana; Carrı̀, Maria Teresa

doi:10.1016/j.nbd.2016.06.006

Cited by 30 publications

(41 citation statements)

References 52 publications

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“…No mutations in these residues have been reported so far 2 . Upon oxidative challenge, full length TDP43 (independently from the presence of ALS-linked mutations) is delocalized from the nucleus to the cytosol and forms both oligomers and large aggregates (Cohen et al, 2012; Bozzo et al, 2016). Studies on the aggregation process have shown that oxidation of cysteines located in the two RRMs decreases protein solubility, leading to the formation of intra and inter-molecular disulfide linkage (Cohen et al, 2012; Chang et al, 2013) and that cysteine residues in RRM1 direct the conformation of TDP43 (Shodai et al, 2013).…”

Section: Cysteine-dependent Aggregation and Mislocalization Of Als Prmentioning

confidence: 99%

“…Formation of large aggregates is driven by oxidative stress and by partial unfolding of the hydrophobic core of the protein, whereas formation of oligomers depends on oxidative stress and clearly relies on accessible cysteine residues (Cohen et al, 2012; Shodai et al, 2013; Bozzo et al, 2016). The role of disulfide bridging as a main determinant of oligomers formation is further supported by the fact that oligomers are readily dissolved by reducing agents and by increasing available GSH (Bozzo et al, 2016), while depletion of the GSH pool induces insolubilization and fragmentation of wild type TDP43 in a motor neuron cell model (Iguchi et al, 2012).…”

Section: Cysteine-dependent Aggregation and Mislocalization Of Als Prmentioning

confidence: 99%

“…The role of disulfide bridging as a main determinant of oligomers formation is further supported by the fact that oligomers are readily dissolved by reducing agents and by increasing available GSH (Bozzo et al, 2016), while depletion of the GSH pool induces insolubilization and fragmentation of wild type TDP43 in a motor neuron cell model (Iguchi et al, 2012). …”

Section: Cysteine-dependent Aggregation and Mislocalization Of Als Prmentioning

confidence: 99%

“…Intriguingly, the two isoforms 35 kDa and 25 kDa deriving from the proteolytic cleavage of full length TDP43, that are found in the insoluble fraction in patients (Neumann et al, 2006) and may represent the truly toxic TDP43 species in mice (Walker et al, 2015), are totally included in cysteine-dependent oligomers (Bozzo et al, 2016). …”

Section: Cysteine-dependent Aggregation and Mislocalization Of Als Prmentioning

confidence: 99%

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Cysteine Modifications in the Pathogenesis of ALS

Valle

Carrı̀

2017

Front. Mol. Neurosci.

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Several proteins are found misfolded and aggregated in sporadic and genetic forms of amyotrophic lateral sclerosis (ALS). These include superoxide dismutase (SOD1), transactive response DNA-binding protein (TDP-43), fused in sarcoma/translocated in liposarcoma protein (FUS/TLS), p62, vasolin-containing protein (VCP), Ubiquilin-2 and dipeptide repeats produced by unconventional RAN-translation of the GGGGCC expansion in C9ORF72. Up to date, functional studies have not yet revealed a common mechanism for the formation of such diverse protein inclusions. Consolidated studies have demonstrated a fundamental role of cysteine residues in the aggregation process of SOD1 and TDP43, but disturbance of protein thiols homeostatic factors such as protein disulfide isomerases (PDI), glutathione, cysteine oxidation or palmitoylation might contribute to a general aberration of cysteine residues proteostasis in ALS. In this article we review the evidence that cysteine modifications may have a central role in many, if not all, forms of this disease.

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Section: Cysteine-dependent Aggregation and Mislocalization Of Als Prmentioning

confidence: 99%

Section: Cysteine-dependent Aggregation and Mislocalization Of Als Prmentioning

confidence: 99%

Section: Cysteine-dependent Aggregation and Mislocalization Of Als Prmentioning

confidence: 99%

Section: Cysteine-dependent Aggregation and Mislocalization Of Als Prmentioning

confidence: 99%

See 2 more Smart Citations

Cysteine Modifications in the Pathogenesis of ALS

Valle

Carrı̀

2017

Front. Mol. Neurosci.

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“…In a recent study we shed new light on the contribution of different species of TDP-43 aggregates in ALS [3]. We demonstrated the existence of two different components, i.e.…”

mentioning

confidence: 87%

Which TDP-43 aggregates are toxic in ALS?

Valle¹,

Carrı̀²

2016

Oncotarget

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TAR DNA‐binding protein 43 oligomers in physiology and pathology

Lye

Chen

2022

IUBMB Life

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TAR DNA‐binding protein 43 (TDP‐43) is an RNA/DNA‐binding protein involved in RNA regulation and diseases. In 2006, TDP‐43 inclusions were found in the disease lesions of several neurodegenerative diseases. It is the pathological hallmark in both amyotrophic lateral sclerosis and frontotemporal lobar dementia. It also presents in a large portion of patients with Alzheimer's disease. TDP‐43 is prone to aggregate; however, the role of TDP‐43 oligomers remains poorly understood in both physiological and pathological conditions. In this review, we emphasize the role of oligomeric TDP‐43 in both physiological and pathological conditions and discuss the potential mechanisms of oligomer formation. Finally, we suggest therapeutic strategies against the TDP‐43 oligomers in neurodegenerative diseases.

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Structural insights into the multi-determinant aggregation of TDP-43 in motor neuron-like cells

Cited by 30 publications

References 52 publications

Cysteine Modifications in the Pathogenesis of ALS

Cysteine Modifications in the Pathogenesis of ALS

Which TDP-43 aggregates are toxic in ALS?

TAR DNA‐binding protein 43 oligomers in physiology and pathology

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