VJNeurology is committed to improving our service to you

Share this video  

VJNeurology is committed to improving our service to you

AAIC 2021 | Protecting cells from misfolding stress to improve cell survival in neurodegenerative disease

Accumulation of aggregated proteins is a hallmark of several neurodegenerative diseases and thus, targeting protein quality control systems to protect cells against a high burden of misfolded protein is emerging as a promising therapeutic strategy. Anne Bertolotti, PhD, FMedSci, MRC Laboratory of Molecular Biology, Cambridge, UK, outlines the work her lab has conducted into understanding this system and developing agents that can boost protein quality control. Guanabenz, an alpha-2 adrenergic agonist used to treat hypertension, was found to improve cell survival in models of neurodegeneration by delaying eIF2a dephosphorylation to protect cells from protein misfolding stress. This effect was related to the activity of guanabenz at R15A. Sephin1 was consequently developed as a derivative that targets R15A but avoids the side effects associated with adrenergic activity. Sephin1 has been used in several proof-of-concept studies in models of neurodegenerative disease. This interview took place during the Alzheimer’s Association International Conference (AAIC) 2021.

Transcript (edited for clarity)

Now that we have this idea about boosting protein quality control, then the question comes, how we’re going to do this? All right. And so, we’ve learned from others, building up on knowledge that an entire field has accumulated over many years. Traditional approaches go about targeting the protein because we think it’s doing a great job, and we could boost it or try to inhibit it or activate it so the system works better...

Now that we have this idea about boosting protein quality control, then the question comes, how we’re going to do this? All right. And so, we’ve learned from others, building up on knowledge that an entire field has accumulated over many years. Traditional approaches go about targeting the protein because we think it’s doing a great job, and we could boost it or try to inhibit it or activate it so the system works better. And this sort of approach is… some approaches along those lines have been developed in the context of protein quality control but they’ve revealed some liabilities, and some deleterious effects. And that has caught my attention because obviously if you want to come up with a treatment for neurodegeneration, right, it needs to be effective, obviously, but it also needs to be safe, because with the exception of ALS, which is rapidly progressive, neurodegenerative diseases, Alzheimer’s, Parkinson’s, Huntington’s is more slowly progressive. So, if you want a treatment, it has to be 100% safe.

So, for this reason coming up with a guess is not going to be necessarily successful. Why? Because the way our cells function has been optimized through billion years of evolution, okay? And what we want to do here, we want to do something… we want to do better than Mother Nature, right? And we don’t have a billion years to play with, okay? So, for these reason, we said okay, we’re not going to be trying to outsmart Mother Nature, billion years of evolution is going to be tricky. So, let’s come up with unbiased approaches.

And so we used cells, any cells, because most cellular processes, protein quality control in particular, are conserved, neurons, brain cells have it, liver cells have it, pancreatic cells have it. All cells have it. So you can use any cells to study the fundamental of it. And so, we in a Petri dish if you like, we recreated the molecular basis of neurodegeneration. Namely massive accumulation of misfolded proteins. And that kills cells. So that is very useful because you can look for approaches that help cell survival.

So, the approach was neurodegeneration is too complex, it’s intractable. Let’s develop an unbiased approach that recapitulates molecular basis of the problem that leads to neurodegeneration, try to find ways to prevent this, and then see if this slows down neurodegeneration. So I must say, initially, in the early years of that, I had people very skeptical thinking you’re not even working neuronal cells, what’s the relevance to neurodegeneration? Well none. We’re targeting common defense mechanisms, all cells have it. I work with cells when I have a robust handle on things. And then … so, we found guanabenz first, the small molecule that protected from protein misfolding stress. It enhanced cell survival by twofold. You have dead cells in one condition and with the compound we have twice as many cells. It tells you you have something really robust in your hands, okay? So, we worked out the mechanism of how it works and found it targets R15A, increasing eIF2a phosphorylation.

And then the thing was that guanabenz was a marketed drug. It been developed in the mid eighties for the treatment of hypertension, so this was very exciting. It’s an existing drug, we could go ahead, but we didn’t go ahead with this because it has been developed for a purpose which has nothing to do with what we are interested in. It’s been developed as an α-2 adrenergic agonist.

So, this molecule has two targets at least. The adrenergic receptor and R15A. And we thought, guanabenz being a hypertensive drug, if we want to treat neurodegeneration, we’re going to have the problem of the hypertensive activity of guanabenz. It does just that. We could see this in mice and we published movies. The mice are all lethargic after their treatment with guanabenz.

So, we then developed a derivative, which is sephin, which has the same properties of guanabenz in cells, and it lacks the adrenergic activity of guanabenz, and we used that compound for proof of concept studies in various models of neurodegenerative diseases. We started this rare peripheral neuropathy, Charcot-Marie-Tooth 1B, and we’ve also reported efficacy of sephin in a SOD1 model of ALS.

Some groups have carried on with guanabenz, despite the adrenergic activity and it’s been really exciting to see this year, this new the clinical trial, Phase II clinical trial in the US that has shown benefits of guanabenz. Obviously, the adrenergic agonist activity, the hypertensive effect on the drug is a problem, but it’s very encouraging for the approach and this result came up month for month, exactly ten years after our initial paper, so I think it’s very encouraging to continue targeting this pathway in this way in particular.

Read more...