(2023) Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction. Our data support that many of the disease associated changes are caused by the fatal familial insomnia D178N mutation corrupting prion protein function.Ĭitation: Foliaki ST, Smith A, Schwarz B, Bohrnsen E, Bosio CM, Williams K, et al. The changes correlate with enhanced wakefulness, which could cause the sleep disturbance. Brain cell dysfunction was associated with stress and abnormal metabolism in such a way as to change critical compounds needed for the brain cells to function correctly. Our findings show that the mutation causes brain cells to dysfunction without the need for mis-folding into prions. Herein, we have used a human brain model to investigate the how this mutation causes brain cell damage. The mis-folding of the prions is caused by a single point mutation, D178N, in the gene encoding the normal precursor protein of the prions, the prion protein. Degeneration of brain cells is associated with accumulation of mis-folded proteins called prions. They further support that many of the disease associated changes are due to a corruption of PrP function and do not require propagation of PrP mis-folding.įatal familial insomnia is a devastating disease characterized by progressively worsening sleep until the brain and body deterioration result in death. Our data strongly suggests that shifting biosynthetic intermediates and oxidative stress, caused by an imbalance of energy supply and demand, results in astrogliosis with compromised neuronal activity in FFI organoids. Using a double mutation (178NN) we could confirm that most changes were caused by the presence of the mutation rather than interaction with PrP molecules lacking the mutation. This increased energy demand in D178N organoids was associated with increased mitophagy and depletion of lipid droplets, in turn resulting in shifts of cellular lipid composition. Underlying these dysfunctions were changes in cellular energy homeostasis, with substantially increased glycolytic and Krebs cycle intermediates, and greater mitochondrial activity. Neuronal electrophysiological function was compromised and levels of neurotransmitters, particularly acetylcholine and GABA, altered. Abnormal post-translational processing of PrP was evident but no tissue deposition or propagation of mis-folded PrP isoforms were observed. We found that, in the absence of other hallmarks of FFI, the D178N organoids exhibited astrogliosis with cellular oxidative stress. Using CRISPR-Cas9 engineered induced pluripotent stem cells, we made D178N cerebral organoids and compared these with isotype control organoids. Consequently, how this mutation exerts its damaging effect on brain cells is still unknown. No in vitro human brain tissue model for this disease has previously been available. Fatal familial insomnia (FFI) is a rare neurodegenerative disease caused by a dominantly inherited single amino acid substitution (D178N) within the prion protein (PrP).
0 Comments
Leave a Reply. |