Unlocking Neuronal Regeneration: Research Reveals New Strategies for Direct Reprogramming
Researchers around Magdalena Götz from Helmholtz Munich have made strides in direct neuronal reprogramming. This innovative approach transforms non-neuronal cells, specifically astrocytes, into functional neurons. Investigating patient-derived cells, the scientists discovered unfolded protein and stress responses hindering efficient reprogramming. The results, published in Neuron, offer hope for treating brain injuries and neurodegenerative diseases.
Direct neuronal reprogramming is a promising avenue to replace neurons lost upon injuries or neurodegenerative diseases via the direct conversion of non-neuronal cells (e.g., glial cells) into functional neurons. However, little is known about the direct conversion of human glial cells, such as astrocytes, and the role of mitochondria, the cell’s powerhouse, whose dysfunctions are often associated to neurological disorders. The group around Magdalena Götz, Head of Stem Cell Center Department at Helmholtz Munich, and Giacomo Masserdotti, senior scientist and last co-author of the study, teamed up with Holger Prokisch’s group from Helmholtz Munich and uncovered challenges in the direct conversion of human cells into functional neurons. Their study was conducted on human astrocytes derived from induced pluripotent stem cells (iPSCs) of healthy individuals and patients carrying mutations in NFUDS4, a protein important for Complex I formation and linked to Leigh Syndrome.
The results showed that astrocytes derived from patients reprogrammed less efficiently than control counterparts. By investigating the molecular mechanisms, the research team unraveled unfolded protein response (UPR) and integrated stress response (ISR), two emergency systems activated in response to the accumulation of unfolded or misfolded proteins, as major general roadblock towards the direct generation of human neurons. In fact, their pharmacological transient inhibition led to the generation of more mature and functional neurons, not only in patients and in control astrocytes, but also when human fibroblasts were reprogrammed.
In this study, the researchers could emphasize the importance of protein balance (proteostasis) mechanisms in direct neuronal reprogramming and the impact of mitochondrial deficits in the conversion process. Remarkably, the identified transient treatments can improve the direct neuronal conversion and, thus, open a new path for the treatment of neurodevelopmental disorders with mitochondrial deficits and for neuronal replacement therapy.
Sonsalla et al. (2024) Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle.