Neurodevelopmental alterations are key drivers of SPG56

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Biallelic pathological variants in CYP2U1 cause SPG56, a rare hereditary spastic paraplegia.
• CYP2U1 is crucial for brain function, involved in arachidonic acid metabolism and lipid hydroxylation.
• Early neurodevelopmental stages in SPG56 remain poorly understood.

Purpose of the Study:

• To investigate the molecular mechanisms and neurodevelopmental impact of SPG56.
• To characterize SPG56 using zebrafish and patient-derived iPSC models.
• To identify key pathogenic pathways in SPG56.

Main Methods:

• Generated and characterized CYP2U1 knock-out zebrafish (cyp2u1-/-).
• Derived and analyzed cortical neurons from SPG56 patient-derived iPSCs.
• Performed transcriptome analysis, local field potential recordings, and whole-brain calcium imaging.

Main Results:

• cyp2u1-/- zebrafish exhibited increased mortality, locomotor impairment, cell cycle defects, increased apoptosis, and bioenergetic deficits.
• Mutant zebrafish showed altered brain network dynamics, including prolonged high-frequency events and skewed neuronal activity.
• Patient-derived neurons and zebrafish models revealed impaired neural network development and similarities in pathogenic mechanisms.

Conclusions:

• Impaired neural network development is a key pathogenic mechanism in SPG56.
• CYP2U1 deficiency leads to significant neurodevelopmental and bioenergetic defects.
• The generated models provide valuable tools for studying SPG56 and related neurodevelopmental disorders.