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ALS Alert Newsletter

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Mar 20
2019

New compounds protect neurons from inflammatory degeneration

Inflammation gets a bad rap. Although too much inflammation can harm or even kill cells, the inflammatory process is also what helps remove clumps of toxic proteins or debris released by neighboring cells as they degenerate. Suppress inflammation and you remove some of the body’s ability to repair itself. What ALS researchers need then, is a way to protect neurons from inflammation’s collateral damage—at least until the underlying pathology had been managed.

A team of Packard scientists, including Lydia Reinhardt and Jared Sterneckert at the Center for Regenerative Therapies at the Technische Universität Dresden in Germany as well as Eric Anderson and Udai Pandey at the University of Pittsburgh Medical Center, identified several compounds that did just that, publishing their work in the journal Stem Cell Reports.

Together with the Lead Discovery Center in Dortmund, they screened a library of 44,000 small molecules for their ability to protect motor neurons from inflammatory-mediated degeneration and identified seven potential compounds. The scientists didn’t know, however, exactly how these molecules worked. In the current study, they found that molecules inhibiting a group of enzymes called cyclin-dependent kinases (CDKs) showed the same pattern of motor neuron protection as the seven compounds identified in their screen. This indicated that the compounds worked by inhibiting CDKs. Looking more closely at the different CDK enzymes, Sterneckert and colleagues found that one of their hit compounds, LDC8, inhibited CDK5, an enzyme known to be active in neurons. Experiments in both mouse and human motor neurons showed that LDC8 rescued these cells from inflammation-induced degeneration.

However, follow-up experiments showed that knocking out CDK5 alone didn’t protect motor neurons from degeneration, which meant that at least one other enzyme must be involved. Searching a database that profiles the activities of different compounds on 400 individual kinases, the researchers identified an enzyme called GSK3β that might also be involved in neuroprotection. Although GSK3β inhibition alone did not protect neurons, blocking the activity of both GSK3β and CDK5 did prevent degeneration from inflammatory stress both in vitro and in vivo.

Compounds inhibiting both enzymes work by protecting the cellular network of microtubules, which helps to give neurons the correct shape and structure they need in order to function properly. The inflammatory molecule nitric oxide alters the microtubule network in neurons, and inhibitors of CDK5 and GSK3β prevent this shape-shifting and the resulting degeneration. Sterneckert and colleagues also identified several other pathways through which dual inhibitors of CDK5 and GSK3β could be neuroprotective, making these compounds promising leads for scientists not just working in ALS but also in Alzheimer’s and other neurodegenerative diseases.