Modeling the effects of ATPase-deficiency of the mitochondrial inner membrane protein ATAD3A in patient-specific neurons

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Modeling the effects of ATPase-deficiency of the mitochondrial inner membrane protein ATAD3A in patient-specific neurons
 
Yang Y1, Woldegebriel R1, Sainio M1, Auranen M12, Ylikallio E12, Tyynismaa H13*
1Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland,
2Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland,
3Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
* Tyynismaa H
      
ATAD3A is a mitochondrial inner membrane AAA ATPase, but without a fully defined function. We recently identified a two-generation family with hereditary spastic paraplegia (HSP) that was caused by a dominant mutation p.G355D in ATAD3A. HSP is a disorder affecting the upper motor neurons and leading to spastic weakness of the lower limbs. ATAD3A mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module, and we showed that the mutation has a dominant-negative effect in vitro as the recombinant mutant ATAD3A protein had a markedly reduced ATPase activity. We further observed that the patient fibroblasts with the ATPase-deficient ATAD3A had elongated mitochondria and substantially increased lysosome mass. These alterations were verified to associate with upregulated basal autophagy through mTOR inactivation, resembling starvation. We have now investigated neurons derived through differentiation of induced pluripotent stem cells, and observed alterations in mitochondrial network dynamics in the patient-specific neurons. We also performed single neuron transcriptomics to identify neuronal gene expression fingerprints caused by the ATPase-deficient ATAD3A. Our finding indicate that patient-specific cell models may be useful in characterizing the effects of ATAD3A dysfunction in neurons, and to help elucidate he precise function of ATAD3A and the mitochondrial target of its ATPase activity.
 

 
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