Hepatocyte transplantation (HTx) corrects selected neurometabolic abnormalities in murine intermediate maple syrup urine disease (iMSUD)

Abstract

Skvorak and coworkers [1] demonstrated the therapeutic efficacy of HTx in a murine model of iMSUD, confirming significant metabolic improvement and survival. To determine the effect of HTx on extrahepatic organs, we examined the metabolic effects of HTx in brain from iMSUD animals. Amino acid analysis revealed that HTx corrected increased ornithine, partially corrected depleted glutamine, and revealed a trend toward alloisoleucine correction. For amino acid and monoamine neurotransmitters, decreased GABA was partially corrected with HTx, while the L-histidine dipeptide of GABA, homocarnosine, was decreased in iMSUD mice and hypercorrected following HTx. Elevated branched chain amino acids (BCAA; leucine, isoleucine, valine) in MSUD can deplete brain tyrosine and tryptophan (the precursors of monoamine neurotransmitters dopamine (DA) and serotonin (5-hydroxytryptamine; 5-HT)) through competition via the large neutral amino acid transporter. HTx corrected decreased DA levels and the DA metabolite, 3-methoxytyramine, and partially corrected the DA intermediate 3,4-dihydroxyphenylacetate (DOPAC) and 5-HT levels, despite normal tyrosine and tryptophan levels in iMSUD mouse brain. We further observed enhanced intracellular turnover of both DA and 5-HT in iMSUD mouse brain, both of which partially corrected with HTx. Our results suggest new pathomechanisms of neurotransmitter metabolism in this disorder and support the therapeutic relevance of HTx in iMSUD mice, while providing proof-of-principle that HTx has corrective potential in extrahepatic organs.

Characterization of 2-(methylamino)alkanoic acid capacity to restrict blood–brain phenylalanine transport in Pahenu2 mice: Preliminary findings

“…The large neutral aminoacidopathies, PKU and MSUD, share many similarities in metabolic neuropathology, yet some rather distinct features [20,21]. In both disorders, as modeled in knockout mice, disturbances in brain amino acid neurotransmitters follow similar patterns, with elevated Gly and depleted Gln, Glu and Asp.…”

“…In both disorders, as modeled in knockout mice, disturbances in brain amino acid neurotransmitters follow similar patterns, with elevated Gly and depleted Gln, Glu and Asp. On the other hand, results for Arg, His and Thr are quite different with respect to disease, with depleted Arg in Pah enu2 mice and elevated brain Arg in mice modeling msud [20], elevated His in the brain of Pah enu2 mice (no demonstrable abnormality in msud mice), and depleted Thr in Pah enu2 mouse brain (elevated in msud mice). Another important observation is that the remaining LNAAs (e.g., Tyr, Trp, Met) are not significantly depleted in murine msud while quite decreased (at least for Tyr and Trp) in the Pah enu2 model.…”

Branched Chain Amino Acids and Maple Syrup Urine Disease

“…Hepatocyte transplantation has been investigated in a mouse model of intermediate MSUD and has shown improved leucine tolerance and extended survival [ 57 ]. The same researchers have recently described direct intrahepatic injections of human amnion epithelial cells performed eight times over the fi rst 35 days of life in their mouse model.…”

Advances and challenges in the treatment of branched‐chain amino/keto acid metabolic defects

“…Norleucine considerably reduced brain α-ketoisocaproic acid levels and preserved energy metabolism as revealed through near-normal brain pyruvate and α-keto glutaric acid concentrations (Zinnanti et al 2009). Hepatocyte transplantation in iMSUD mice, with approximately 3% repopulation of the endogenous liver with wild-type hepatocytes, corrects selected neurometabolic abnormalities in both the dopaminergic and serotoninergic systems, and concomitantly increases lifespan and body weight, which points to the potential therapeutic relevance of hepatocyte transplantation in humans (Skvorak et al 2009a; Skvorak et al 2009b). …”