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In Search for ALS Therapies, Researchers Turn to Protein Interactions

Amyotrophic lateral sclerosis (ALS) — also known as Lou Gehrig’s disease — is a progression motor neuron disease characterized by loss of muscle tissue and impaired movement. The genetic underpinnings of the disease are complex and not understood for many patients. To date, almost 150 genes have been linked with the disease. Determining how these genes and their proteins interact is vitally important for identifying new therapeutic targets moving forward.

Recent findings from Northwestern University published in Scientific Reports shed new light on the complex network of protein interactions in patients suffering from sporadic ALS or ALS with TDP43. Through statistical analysis of both the ALS mutations and protein interactions, the researchers identified key pathways associated with the disease progression. These patterns of protein expression help explain why patients with different mutations can show similar symptoms and disease pathology.

In this report, the authors argue that protein interactions represent a highly relevant and actionable area of study in the search for ALS therapies:

“By shifting our attention from genes to proteins and to their interactions, we may begin to understand the cellular events that are perturbed due to different mutations, and the underlying consequences that lead to neuronal vulnerability and progressive degeneration.”

As previously observed and reported in ALS patients, the researchers found statistical correlation between disease state and pathways regulating lipid and fatty acid homeostasis in neurons. Perturbation of the peroxisome proliferator-activated receptor (PPAR) family of proteins — in particular, increased expression of the upstream regulator PPAR gamma — was observed in all 17 unrelated cases of ALS studied.

Elevated expression of the PPAR gamma protein in the Betz cells of ALS patients was confirmed by immunocytochemical analysis using the Bioss PPAR Gamma Polyclonal Antibody.

The authors also identified the protein YWAHZ as “one of the common neuronal defects observed in vulnerable and diseased upper motor neurons.” The 14-3-3 family of proteins, of which YWAHZ is a member, are key signal transducers and facilitate ER trafficking. Reduction of YWAHZ has been shown to induce ER stress and, in addition to its role in neurodegeneration, has been observed in rat models of epilepsy.

Immunocytochemical analysis using the Bioss YWHAZ (1B6) Monoclonal Antibody confirmed that YWAHZ expression was significantly reduced in the Betz cells of ALS patients with both sporadic and TDP43 pathology.

In addition to these targets, the authors found altered protein expression across several other canonical pathways, including those responsible for responding to hypoxic insult and DNA damage.

“The distribution of ALS proteins among known canonical pathways, suggested the importance of maintaining homeostasis for lipids, proteins, preparing the cell for a potential DNA damage, hypoxic insult, and ensuring cytoarchitectural integrity and stability,” the authors wrote.

Read the full report in Scientific Reports:

Protein-protein interactions reveal key canonical pathways, upstream regulators, interactome domains, and novel targets in ALS


 

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14-3-3 Tau WB, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-12419R
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ErbB4 WB, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-10226R
ErbB4 FCM, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-1085R
ErbB4 (Tyr1056) WB, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-13094R
ErbB4 (Tyr1258) WB, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-13093R
ErbB4 (Tyr984) WB, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-3184R
FIG4 WB, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-11690R
FUS WB, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-2980R
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Hsc70 WB, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-5117R
NEK1 WB, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-7814R
OPRS1 WB, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-5111R
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Senataxin WB, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-11693R
SOD1 WB, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-10216R
SQSTM1 WB, IHC-P, IF(IHC-P) Hu, Ms, Rt bs-2951R
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