Blockages in Nerve-cell Protein ‘Factory’ Implicated in Neurodegenerative Disease

Photo of Jon AudhyaA molecular basis underlying the neurodegenerative condition hereditary spastic paraplegia (HSP) has been identified in a study by numerous Integrated Program in Biochemistry (IPiB) faculty members, students, and collaborators. The research, published in Cell Reports, shows how a mutation in the TFG gene – one of several linked to HSP – impairs neurons from forming the structures needed to transmit signals properly.

Hereditary spastic paraplegia includes several inherited disorders that make walking difficult to impossible.

To make an arm or a leg move, neurons – up to one meter in length – are required to send the brain’s signal to the limb through cell extensions called axons. Individuals with early-onset HSP begin to lose signaling to their legs during infancy and are often never able to walk. Advances in genome sequencing have linked more than 70 genes to HSP development, but their individual contributions to the disease state have never been clear.

“The main approach people have used in the past is to overexpress a mutant protein in a generic immortalized cell line, and then see the impact on cellular physiology. We took a different strategy by first engineering the mutation into human stem cells and then differentiating those cells into human neurons,” said Anjon Audhya professor of biomolecular chemistry and senior author on the study. “The major implication of this work is that we found a result you could never identify using a standard cell line.”

Audhya and his team first used CRISPR-mediated gene editing in induced pluripotent stem cells (iPSCs) to introduce a TFG mutation found in hereditary spastic paraplegia patients. Then, they differentiated the stem cells to develop into cortical neurons, the same type of neurons affected in these patients.

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