RESUMO
Transactive response DNA binding protein of 43 kDa (TDP-43) pathology is a common proteinopathy observed among a broad spectrum of patients with neurodegenerative disease, regardless of the mutation. This suggests that protein-protein interactions of TDP-43 with other proteins may in part be responsible for the pathology. To gain better insights, we investigated TDP-43-binding proteins in each domain and correlated these interactions with canonical pathways. These investigations revealed key cellular events that are involved and are important at each domain and suggested previously identified compounds to modulate key aspects of these canonical pathways. Our approach proposes that personalized medicine approaches, which focus on perturbed cellular mechanisms would be feasible in the near future.
Assuntos
Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Proteinopatias TDP-43 , Humanos , Proteinopatias TDP-43/genética , Proteinopatias TDP-43/metabolismo , Proteinopatias TDP-43/patologia , Medicina de Precisão , Proteínas de Ligação a DNA/metabolismo , MutaçãoRESUMO
Even though amyotrophic lateral sclerosis (ALS) is a disease of the upper and lower motor neurons, to date none of the compounds in clinical trials have been tested for improving the health of diseased upper motor neurons (UMNs). There is an urgent need to develop preclinical assays that include UMN health as a readout. Since ALS is a complex disease, combinatorial treatment strategies will be required to address the mechanisms perturbed in patients. Here, we describe a novel in vitro platform that takes advantage of an UMN reporter line in which UMNs are genetically labeled with fluorescence and have misfolded SOD1 toxicity. We report that NU-9, an analog of the cyclohexane-1,3-dione family of compounds, improves the health of UMNs with misfolded SOD1 toxicity more effectively than riluzole or edaravone, -the only two FDA-approved ALS drugs to date-. Interestingly, when NU-9 is applied in combination with riluzole or edaravone, there is an additive effect on UMN health, as they extend longer axons and display enhanced branching and arborization, two important characteristics of healthy UMNs in vitro.
Assuntos
Esclerose Lateral Amiotrófica , Riluzol , Esclerose Lateral Amiotrófica/tratamento farmacológico , Animais , Edaravone/farmacologia , Humanos , Camundongos , Neurônios Motores , Riluzol/farmacologia , Riluzol/uso terapêutico , Superóxido DismutaseRESUMO
Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein-protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as "causative" for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration-approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.