Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Abstract

Glutaric acidemia type I (GA I) is an inherited neurometabolic disease caused by deficient activity of the mitochondrial enzyme glutaryl‐CoA dehydrogenase (GCDH), resulting in predominant accumulation of glutaric and 3‐hydroxyglutaric acids derived from lysine (Lys), hydroxylysine, and tryptophan catabolism. GA I patients usually present progressive cortical leukodystrophy and frequently develop acute striatal degeneration during encephalopathic crises during the first three years of life. The pathophysiology of the neurodegeneration observed in GA I is still partly known, although the development of the genetic mice model of GA I (Gcdh−/−) has contributed to clarify potential underlying mechanisms involved in brain damage in this disease. In this review we will summarize the knowledge acquired from studies using this animal model indicating that disruption of redox homeostasis, glutamatergic neurotransmission and bioenergetics, as well as vascular alterations, blood‐brain barrier breakage and altered myelination underlie the cortical and striatum abnormalities and white matter changes observed in GA I patients. Elucidation of these pathomechanisms potentially offers new standpoints for the development of novel therapeutic strategies for this disease.

Elevated levels of BDNF and cathepsin‐das possible peripheral markers of neurodegeneration in plasma of patients with glutaric acidemia type I

“…It should be also noted that GA1 patients present high levels of proinflammatory cytokines (Guerreiro et al, 2018), as well as marked elevation of various parameters of oxidative stress in plasma and urine (Guerreiro et al, 2015;Mescka et al, 2013). In line with these findings, disturbance of redox homeostasis, glutamatergic neurotransmission, vascular alterations, and inflammatory processes were also observed in cortex and striatum of the GA1 knockout animal model (Amaral et al, 2015;Rodrigues et al, 2016;Wajner et al, 2019). It was also demonstrated that disturbance of redox homeostasis were associated with inflammatory processes induced by quinolinic acid administration in striatum of these mice subjected to dietary lysine overload (Seminotti et al, , 2014.…”

“…Regarding its pathophysiology, a great number of studies indicate that the major accumulating organic acids, namely GA and 3OHGA, are neurotoxic causing mainly oxidative stress, disturbances of the glutamatergic, and GABAergic systems and of mitochondrial energetic metabolism (Kolker et al, 2015;Wajner, 2019;Wajner, Amaral, Leipnitz, & Seminotti, 2019); but, so far, to the best of our knowledge, no peripheral biochemical marker of degeneration has been reported in this disease. Patients affected by GA1 have severe neurological symptoms and brain abnormalities whose pathophysiology is poorly known.…”

Nuclear Factor Erythroid-2-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders

“…A great amount of evidence shows that oxidative stress contributes to the pathogenesis of the neurological dysfunction in various IMDs ( Mc Guire et al, 2009 ; Ribas et al, 2014 ; Wajner et al, 2020 ). Biomarkers of lipid, protein and DNA oxidative damage and altered antioxidant defenses, have been demonstrated in in vitro and in vivo disease models, as well as in cells of patients affected by these disorders ( Mc Guire et al, 2009 ; Halliwell and Gutteridge, 2015 ; Faverzani et al, 2017 ; Parmeggiani and Vargas, 2018 ; Richard et al, 2018 ; Wajner et al, 2019 , 2020 ).…”

“…In this scenario, it has been widely demonstrated that the metabolites accumulated in some inherited neurometabolic disorders, including amino acids, organic acids and acylcarnitines, act as neurotoxins and cause mitochondrial dysfunction leading to augmented generation of reactive species. Many of these neurotoxins disrupt mitochondrial homeostasis by causing disturbances in electron transport chain, which lead to increased electron leakage and a consequent overproduction of ROS ( Wajner et al, 2004 , 2019 , 2020 ; Berger et al, 2014 ; Ribas et al, 2014 ; Leipnitz et al, 2015 ; Wyse et al, 2021 ). Therefore, the quantification of oxidative stress biomarkers may provide an approach for monitoring of redox status in individuals affected by IMDs and elucidation of a possible role of mitochondrial dysfunction in these disorders ( Mc Guire et al, 2009 ; Leipnitz et al, 2015 ).…”

“…Exposing Gcdh –/– animals to high protein or Lys intake resulted in elevated serum and brain GA and 3HGA accumulation, as well as neuronal loss, myelin disruption and gliosis mostly in the striatum and deep cortex ( Zinnanti et al, 2006 , 2007 ). Therefore, the Gcdh –/– mouse model exposed to Lys overload has been preferentially used as an appropriate GA I animal model to study the neuropathology of this disorder ( Wajner et al, 2019 ). Different approaches were used to achieve high Lys levels in these animals, including Lys intraperitoneal or intracerebral injections, as well as chow supplemented with Lys ( Zinnanti et al, 2006 ; Wajner et al, 2019 ).…”