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Department of Physiology, Development and Neuroscience


An interdisciplinary team of University of Cambridge researchers have developed a novel human brain organoid model for amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). The work led by senior author Dr András Lakatos in the Department of Clinical Neurosciences and first author, Dr Kornélia Szebényi, a postdoctoral researcher in Dr Lakatos’s lab, has been published in Nature Neuroscience.

ALS and FTD are fatal and rapidly progressing neurological conditions, that lead to muscle paralysis and cognitive decline. There are currently no treatments that can stop or reverse the disease, and the therapeutic treatment development had been hampered by the lack of human models for investigating cell-type specific mechanisms that lead to cell death. Dr. Szebényi grew human-derived mini-brains from stem cell lines of ALS/FTD patients. With contributions from PhD student Lea Wenger, they show that organoids displayed the cell-type diversity relevant to disease and recapitulated the cortical architecture. PDN researchers Alex Dunn, Susanna Mierau and Ole Paulsen provided evidence from electrophysiological recordings of neuronal activity that the cortical organoids form functional neuronal communication networks.

The human brain organoids affected by a common genetic ALS/FTD mutation revealed early cell vulnerabilities. This is aligned with the emerging observation that cell damage occurs early, before the onset of symptoms in patients. The organoids further captured the initial cell-type specific events. Deep layer cortical neurons accumulated a toxic protein impairing cell survival while astrocytes developed homeostasis disturbances, which may indirectly cause neuronal damage. In collaboration with Dr Gabi Balmus’s group (UKDRI) the research team showed that the vulnerability to damage may be due, at least in part, to DNA repair failure, which could be partially prevented as shown in this study. The official University Press Release can be found here.