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1.
Sci Rep ; 12(1): 8140, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35581326

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure or effective treatment in which TAR DNA Binding Protein of 43 kDa (TDP-43) abnormally accumulates into misfolded protein aggregates in affected neurons. It is widely accepted that protein misfolding and aggregation promotes proteotoxic stress. The molecular chaperones are a primary line of defense against proteotoxic stress, and there has been long-standing interest in understanding the relationship between chaperones and aggregated protein in ALS. Of particular interest are the heat shock protein of 70 kDa (Hsp70) family of chaperones. However, defining which of the 13 human Hsp70 isoforms is critical for ALS has presented many challenges. To gain insight into the specific Hsp70 that modulates TDP-43, we investigated the relationship between TDP-43 and the Hsp70s using proximity-dependent biotin identification (BioID) and discovered several Hsp70 isoforms associated with TDP-43 in the nucleus, raising the possibility of an interaction with native TDP-43. We further found that HspA5 bound specifically to the RNA-binding domain of TDP-43 using recombinantly expressed proteins. Moreover, in a Drosophila strain that mimics ALS upon TDP-43 expression, the mRNA levels of the HspA5 homologue (Hsc70.3) were significantly increased. Similarly we observed upregulation of HspA5 in prefrontal cortex neurons from human ALS patients. Finally, overexpression of HspA5 in Drosophila rescued TDP-43-induced toxicity, suggesting that upregulation of HspA5 may have a compensatory role in ALS pathobiology.


Assuntos
Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Esclerose Lateral Amiotrófica/metabolismo , Animais , Proteínas de Ligação a DNA/metabolismo , Drosophila/metabolismo , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Chaperonas Moleculares
2.
RSC Chem Biol ; 2(4): 1158-1166, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34458829

RESUMO

Tar DNA binding (TDP)-43 proteinopathy, typically described as cytoplasmic accumulation of highly modified and misfolded TDP-43 molecules, is characteristic of several neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE). TDP-43 proposed proteinopathies include homeostatic imbalance between nuclear and cytoplasmic localization, aggregation of ubiquitinated and hyper-phosphorylated TDP-43, and an increase in protein truncation of cytoplasmic TDP-43. Given the therapeutic interest of targeting TDP-43, this review focuses on the current landscape of strategies, ranging from biologics to small molecules, that directly target TDP-43. Antibodies, peptides and compounds have been designed or found to recognize specific TDP-43 sequences but alleviate TDP-43 toxicity through different mechanisms. While two antibodies described here were able to induce degradation of pathological TDP-43, the peptides and small molecules were primarily designed to reduce aggregation of TDP-43. Furthermore, we discuss promising emerging therapeutic targets.

3.
Channels (Austin) ; 12(1): 219-227, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30081699

RESUMO

Drug discovery campaigns directly targeting the voltage-gated sodium channel NaV1.7, a highly prized target in chronic pain, have not yet been clinically successful. In a differentiated approach, we demonstrated allosteric control of trafficking and activity of NaV1.7 by prevention of SUMOylation of collapsin response mediator protein 2 (CRMP2). Spinal administration of a SUMOylation incompetent CRMP2 (CRMP2 K374A) significantly attenuated pain behavior in the spared nerve injury (SNI) model of neuropathic pain, underscoring the importance of SUMOylation of CRMP2 as a pathologic event in chronic pain. Using a rational design strategy, we identified a heptamer peptide harboring CRMP2's SUMO motif that disrupted the CRMP2-Ubc9 interaction, inhibited CRMP2 SUMOylation, inhibited NaV1.7 membrane trafficking, and specifically inhibited NaV1.7 sodium influx in sensory neurons. Importantly, this peptide reversed nerve injury-induced thermal and mechanical hypersensitivity in the SNI model, supporting the practicality of discovering pain drugs by indirectly targeting NaV1.7 via prevention of CRMP2 SUMOylation. Here, our goal was to map the unique interface between CRMP2 and Ubc9, the E2 SUMO conjugating enzyme. Using computational and biophysical approaches, we demonstrate the enzyme/substrate nature of Ubc9/CRMP2 binding and identify hot spots on CRMP2 that may form the basis of future drug discovery campaigns disrupting the CRMP2-Ubc9 interaction to recapitulate allosteric regulation of NaV1.7 for pain relief.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Mapas de Interação de Proteínas , Enzimas de Conjugação de Ubiquitina/metabolismo , Regulação Alostérica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/genética , Canal de Sódio Disparado por Voltagem NAV1.7/química , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Enzimas de Conjugação de Ubiquitina/química , Enzimas de Conjugação de Ubiquitina/genética
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