Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria.

Abstract

Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of heme biosynthesis due to a pathogenic mutation in the Hmbs gene, resulting in half-normal activity of hydroxymethylbilane synthase. Factors that induce hepatic heme biosynthesis induce episodic attacks in heterozygous patients. The clinical presentation of acute attacks involves the signature neurovisceral pain and may include psychiatric symptoms. Here we used a knock-in mouse line that is biallelic for the Hmbs c.500G > A (p.R167Q) mutation with ~ 5% of normal hydroxymethylbilane synthase activity to unravel the consequences of severe HMBS deficiency on affective behavior and brain physiology. Hmbs knock-in mice (KI mice) model the rare homozygous dominant form of AIP and were used as tool to elucidate the hitherto unknown pathophysiology of the behavioral manifestations of the disease and its neural underpinnings. Extensive behavioral analyses revealed a selective depression-like phenotype in Hmbs KI mice; transcriptomic and immunohistochemical analyses demonstrated aberrant myelination. The uncovered compromised mitochondrial function in the hippocampus of knock-in mice and its ensuing neurogenic and neuroplastic deficits lead us to propose a mechanistic role for disrupted mitochondrial energy production in the pathogenesis of the behavioral consequences of severe HMBS deficiency and its neuropathological sequelae in the brain.

• Authors: Stefanie Berger, Miranda Stattmann, Ana Cicvaric, Francisco J Monje, Pierluca Coiro, Matej Hotka, Gerda Ricken, Johannes Hainfellner, Susanne Greber-Platzer, Makiko Yasuda, Robert J Desnick, Daniela D Pollak
• Journal: Acta neuropathologica communications (Acta Neuropathol Commun) Vol. 8 Issue 1 Pg. 38 (03 20 2020) ISSN: 2051-5960 [Electronic] England
• PMID: 32197664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hydroxymethylbilane Synthase

Topics

• Anhedonia
• Animals
• Behavior, Animal
• Cell Proliferation
• Depression (genetics, metabolism, physiopathology, psychology)
• Disease Models, Animal
• Elevated Plus Maze Test
• Gene Knock-In Techniques
• Hindlimb Suspension
• Hippocampus (metabolism, physiopathology)
• Homozygote
• Hydroxymethylbilane Synthase (genetics)
• Immunohistochemistry
• Long-Term Potentiation
• Mice
• Microscopy, Fluorescence
• Mitochondria (metabolism)
• Myelin Sheath (metabolism)
• Neural Inhibition
• Neural Stem Cells
• Neurogenesis
• Neuronal Plasticity
• Patch-Clamp Techniques
• Porphyria, Acute Intermittent (genetics, metabolism, physiopathology, psychology)