Abstract Individuals with sickle cell disease (SCD) suffer from a high burden of neurocognitive impairment. Cerebrovascular lesions, characterized by diffusion tensor imaging (DTI) identified neuroaxonal damage, are associated with learning and memory deficits. The molecular and cellular intermediates driving microstructural neuroaxonal damage and cognitive impairment in SCD remains largely unexplored. Herein, we report that SCD mice (SS) have reduced expression of frataxin (FXN), a mitochondrial protein, in their astrocytes compared to normal control (AA) mice. A newly generated sickle bone marrow chimera mice with astrocyte-specific deletion of FXN (SSFXN-KO) showed worsening white matter neuroaxonal damage compared to the normal mice lacking astrocytic FXN (AAFXN-KO) as well as to the SS mice with wild-type FXN expression (SSFXN-WT). The SSFXN-KO mice exhibited impaired cognitive function assessed by the functional novel object recognition tests. Induction of FXN improved cognitive responses in the SS mice. Overall, our data demonstrate that astrocytic FXN plays a pivotal role in regulating neuroaxonal health and cognitive function in SCD.
Novelli et al. (Wed,) studied this question.