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Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu,Zn-superoxide dismutase Cell Biology
Cu, Zn superoxide dismutase (SOD1) is one of the genes implicated in the devastating neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Although the precise mechanisms of SOD1 mutant (SOD1mut)-induced motoneuron toxicity are still unclear, defects in SOD1 proteostasis are known to have a critical role in ALS pathogenesis. We previously reported that the SOD1mut adopts a conformation that exposes a Derlin-1–binding region (DBR) and that DBR-exposed SOD1 interacts with Derlin-1, leading to motoneuron death. We also found that an environmental change, i.e. zinc depletion, induces a conformational change in WT S...
Source: Journal of Biological Chemistry - March 5, 2020 Category: Chemistry Authors: Kengo Homma, Hiromitsu Takahashi, Naomi Tsuburaya, Isao Naguro, Takao Fujisawa, Hidenori Ichijo Tags: Molecular Bases of Disease Source Type: research

LOF and GOF Mechanisms of TDP-43 Proteinopathies Neurobiology
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) are two clinically distinct neurodegenerative conditions sharing a similar histopathology characterized by the nuclear clearance of TDP-43 and its associated deposition into cytoplasmic inclusions in different areas of the central nervous system. Given the concomitant occurrence of TDP-43 nuclear depletion and cytoplasmic accumulation, it has been proposed that TDP-43 proteinopathies originate from either a loss-of-function (LOF) mechanism, a gain-of-function (GOF) process, or both. We have addressed this i...
Source: Journal of Biological Chemistry - September 8, 2016 Category: Chemistry Authors: Cascella, R., Capitini, C., Fani, G., Dobson, C. M., Cecchi, C., Chiti, F. Tags: Molecular Bases of Disease Source Type: research

Quantification of the Relative Contributions of Loss-of-function and Gain-of-function Mechanisms in TAR DNA-binding Protein 43 (TDP-43) Proteinopathies Neurobiology
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) are two clinically distinct neurodegenerative conditions sharing a similar histopathology characterized by the nuclear clearance of TDP-43 and its associated deposition into cytoplasmic inclusions in different areas of the central nervous system. Given the concomitant occurrence of TDP-43 nuclear depletion and cytoplasmic accumulation, it has been proposed that TDP-43 proteinopathies originate from either a loss-of-function (LOF) mechanism, a gain-of-function (GOF) process, or both. We have addressed this i...
Source: Journal of Biological Chemistry - September 8, 2016 Category: Chemistry Authors: Roberta Cascella, Claudia Capitini, Giulia Fani, Christopher M. Dobson, Cristina Cecchi, Fabrizio Chiti Tags: Molecular Bases of Disease Source Type: research