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Bringing a treatment closer to patients

Updated: Jan 17, 2022

Dr. Gerardo Morfini and his co-workers at the University of Illinois study the basic biology of neurodegenerative diseases. One area of interest to his laboratory is axon transport, the movement of molecules up and down the axoplasm, the axoplasm is located inside the long fibers that go from the nerve body to other nerves, muscles, or organs. Uniquely, Morfini uses the giant squid in much of his work. Dr. Morfini studies stress-activated protein kinases, these enzymes are primarily activated through extracellular stresses and cytokines. Kinases effect how molecules move in the cell. NDR awarded Dr. Morfini $256,000 in 2020 to show that the same basic biologic principles of axon signaling that are observed in the squid axoplasm are also seen in cultured neurons from ALS mice and ultimately, in live mice. He found that decreasing an enzyme, p38a, restored function in axon transport and it could be a therapeutic strategy for treating ALS patients. To test his hypothesis, he genetically altered mice to prevent activation of mutant p38a and measured how quickly they fall off a moving rod. His theory is that this alteration represents a clinically relevant scenario for using brain-permeable, orally active p38a inhibitors (like MW150) to treat ALS. His work is hopeful for developing ALS treatments and illustrates the tremendous effort and foundation that must be in place before bringing a treatment to patients.


Gender-dependent contributions of p38a signaling to the onset of locomotor deficits in the SOD1-G93A mouse model of ALS.

To evaluate a potential role of the protein kinase p38a on locomotor deficits elicited by mutant SOD1G93A expression in vivo, we used a genetic approach. Specifically, we performed crosses between transgenic SOD1G93A mice, a well-established ALS mouse model, and p38a AF/WT mice. In these later mice, regulatory residues threonine 180 and tyrosine 182 of an endogenous p38a allele were mutated to alanine and phenylalanine, respectively (AF mutations). These mutations preclude activation of mutant p38a protein by upstream MAPK kinases. As a result of these mutations, p38aAF/WT mice feature ubiquitous attenuation of p38a signaling. Such attenuation represents a potentially relevant clinically scenario for the use of brain-permeable, orally active p38a inhibitors (i.e., MW150) to treat ALS.

Mice corresponding to four genotypes (WT, p38aAF/WT, SOD1G93A and SOD1G93A:p38aAF/WT mice) were evaluated using Rotarod assays. Plots display the latency of mice to fall from a moving rod (measured in seconds, Y axis) as a function of age (X axis). Partial results (updated on 2022-01-14) are shown for male and female mice (top and lower plots, respectively). The experiment will be concluded by the end of March 2022, when over 15 mice/gender/group have been analyzed.

Starting at postnatal (P) age P82-92, SOD1G93A male mice displayed decreased latency to fall, compared to WT male mice. Remarkably, the onset of locomotor deficits was delayed until postnatal age P117-129 in SOD1G93A male mice featuring ubiquitous attenuation of p38a signaling (SOD1G93A:p38aAF/WT mice). Dotted area highlights the age gap where p38a attenuation appears to provide a protective effect.

As expected from prior studies, the onset of locomotor deficits was slightly delayed in SOD1G93A female mice, compared to SOD1G93A male mice. Compared to WT female mice, SOD1G93A female mice displayed decreased latency to fall starting at age P103-113. Unlike males, ubiquitous attenuation of p38 protective effects of signaling did not delay the onset of locomotor symptoms in SOD1G93A:p38aAF/WT female mice.

Data were analyzed using a Two-way ANOVA repeated measure and Tukey's multiple comparisons test. Data is expressed as mean±SME. Blue asterisks (*) indicate statistically significant differences between WT and SOD1G93A phenotypes (p<0.05). Red asterisks (*) indicate statistically significant differences between WT and SOD1G93A:p38alphaAF/WT phenotypes (p<0.05).

Data were generated by Drs. Victoria Occhieppo, Mercedes Priego, and Lisa Hoffman at the laboratory of Dr. Gerardo Morfini (University of Illinois). Funding for these experiments provided by NDR and an NIH award (R21NS120126) to GM.

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