Glia
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Severe neurological symptoms, cerebral edema, and atrophy are common features of the inherited metabolic disorder maple syrup urine disease (MSUD). However, the pathomechanisms involved in the neuropathology of this disease are not well established. In this study, we investigated the effects of the branched-chain keto acids (BCKA) alpha-ketoisocaproic (KIC), alpha-ketoisovaleric (KIV), and alpha-keto-beta-methylvaleric (KMV), which accumulate in MSUD, on astrocyte morphology and cytoskeleton reorganization. ⋯ Furthermore, the effects of BCKA on astrocyte morphology were prevented by creatine. In addition, creatine kinase activity was inhibited by KIC and KIV; this inhibition was prevented by creatine, indicating that these keto acids compromise brain energy metabolism. Considering that astroglial cells are critical to brain development and functioning, it is conceivable that alterations of the actin network by BCKA may have important implications in astrocytic function and possibly in the pathogenesis of the neurological dysfunction and brain damage of MSUD patients.