Investigators Reveal Key Protein, ACTIVIN-A, for Growth of Brain Neurons Associated With Alzheimer and Parkinson Disease

A newly published study in Nature Biotechnology identified a protein key to the development of central norepinephrine (NE) neurons, located mainly in the locus coeruleus (LC), which play an essential role in neurological conditions such as Alzheimer disease (AD) and Parkinson disease (PD). Following this finding, investigators grew the neurons from stem cells. These results show the availability of functional human LC-NE neurons and enable further exploration of their roles in psychiatric and neurodegenerative diseases as well as offer a tool for future therapeutic development.¹

Investigators identified ACTIVIN-A, belonging to a family of growth factors, as an important protein in regulating neurogenesis in human NE neurons. They then developed a method to generate 40% to 60% human LC-NE neurons from human pluripotent stem cells, which depended on the identification of ACTIVIN-A in regulating LC-NE transcription factors in dorsal rhombomere 1 progenitors. Using the identified protein and a series of additional signals, the investigators then directed the cell development toward the production of LC-NE neurons.

“The norepinephrine neurons in the locus coeruleus are essential for our life. We call it the life center. Without these nerve cells, we would probably be extinct from Earth,” senior author Su-Chun Zhang, MD, PhD, a professor of neuroscience and neurology at University of Wisconsin (UW)–Madison, said in a statement.² “If this is somewhat causative, then we could potentially do something to prevent or delay the neurodegeneration process. The application of these cells is quite broad in its significance."

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Once the cells were converted, they showed typical characteristics of functioning LC-NE neurons in the human brain and released the neurotransmitter norepinephrine. The produced cells also showed extensive axonal arborization, which is an extension of the long, branching arms of neurons that enables the connections between brain cells, and uptake NE. In addition, the cells reacted to the presence of carbon dioxide, which is critical for breathing control, exhibiting chemoreceptor activity, pacemaker activity, and calcium oscillation.

“People have noticed this for a long time, but they don’t know what the function of the locus coeruleus is in this process. And partly because we don’t have a good model to mimic the human LC-NE neurons,” lead author Yunlong Tao, PhD, an investigator at Nanjing University in China and former assistant research professor at UW–Madison’s Waisman Center, said in a statement.² “We have some new understanding about locus coeruleus development. That’s the major finding in this paper, and based on that finding, we are able to generate locus coeruleus norepinephrine neurons.”

Furthermore, the single-nucleus RNA sequencing analysis at multiple time points confirmed NE cell identity and showed the differentiation trajectory from hindbrain progenitors to NE neurons via an ASCL1-expressing precursor stage. Additionally, the LC-NE neurons engineered with an NE sensor reliably reported extracellular levels of NE. Previously, investigators attempted to create these neurons from human stem cells which followed a protocol based on the development of LC-NE neurons in mouse models. For 2 years, Tao and colleagues explored why these attempts failed and how development of the neurons from stem cells was different in humans.

Based on the findings from the new study, the authors suggest the produced cells may serve as models for disease in humans, allowing other researchers to screen therapies for potential treatments and analyze why the cells in the locus coeruleus die so early in neurodegenerative diseases. In the next steps, the researchers from the current study plan to assess the detailed mechanisms through which ACTIVIN-A regulates LC-NE neuron development. The authors also will use the cells for the translational work of treatment screening and disease modeling, according to a statement.2

REFERENCES
1. Tao Y, Li X, Dong Q, et al. Generation of locus coeruleus norepinephrine neurons from human pluripotent stem cells. Nat Biotechnol. Published online November 16, 2023. doi:10.1038/s41587-023-01977-4
2. Rivera-Bonet CN. Scientists produce human norepinephrine neurons from stem cells, with significant implications for researching diseases like Alzheimer’s and Parkinson’s. News Release. University of Wisconsin–Madison. Published November 17, 2023. Accessed December 21, 2023. https://news.wisc.edu/scientists-produce-human-norepinephrine-neurons-from-stem-cells-with-significant-implications-for-researching-diseases-like-alzheimers-and-parkinsons/