NAD metabolism in HPRT-deficient mice

Micheli, Vanna; Jacomelli, Gabriella; Marcello, Federica Di; Notarantonio, L.; Sestini, Silvia; Cerboni, Barbara; Bertelli, Matteo; Pompucci, G; Jinnah, Hyder A.

doi:10.1007/s11011-009-9134-9

Cited by 8 publications

(9 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A pharmacological model, the 6-hydroxydopamine-treated rat, in which catecholamine-containing neurons were destroyed, showed self-injurious behavior in response to DOPA-agonist administration, supporting the connection between selfinjurious behaviour and DA deficit [109]. A genetic model, the HPRT-knockout mouse also mentioned above [103], did not show neurobehavioral alterations, but presented an agerelated decreased content of DA in the brain [110]. DA deficit has been confirmed in various HPRT-deficient cell cultures developed to study the effects of the enzyme deficit and of purine alterations [107,111,112].…”

Section: Hypoxanthine-guanine Phosphoribo-syltransferase Deficiency Amentioning

confidence: 89%

“…By contrast decreased NAD, ATP and GTP concentrations and increased NAD production from nicotinic acid were measured in LNS fibroblasts [93]. NAD concentration and enzyme activities committed to its metabolism were found to be significantly increased in liver, but not in brain or blood of HPRT-knockout mice, animal models of LNS [103]. Together these findings suggest that disturbed pyridine metabolism accompanies the purine perturbation associated to HPRT deficiency in different cell types and lead to hypothesize the possible involvement of NAD and PARP in LNS neurological symptoms.…”

Section: Hypoxanthine-guanine Phosphoribo-syltransferase Deficiency Amentioning

confidence: 91%

See 1 more Smart Citation

Neurological Disorders of Purine and Pyrimidine Metabolism

Micheli

Camici²,

Tozzi³

et al. 2011

CTMC

Self Cite

101

View full text Add to dashboard Cite

Purines and pyrimidines, regarded for a long time only as building blocks for nucleic acid synthesis and intermediates in the transfer of metabolic energy, gained increasing attention since genetically determined aberrations in their metabolism were associated clinically with various degrees of mental retardation and/or unexpected and often devastating neurological dysfunction. In most instances the molecular mechanisms underlying neurological symptoms remain undefined. This suggests that nucleotides and nucleosides play fundamental but still unknown roles in the development and function of several organs, in particular central nervous system. Alterations of purine and pyrimidine metabolism affecting brain function are spread along both synthesis (PRPS, ADSL, ATIC, HPRT, UMPS, dGK, TK), and breakdown pathways (5NT, ADA, PNP, GCH, DPD, DHPA, TP, UP), sometimes also involving pyridine metabolism. Explanations for the pathogenesis of disorders may include both cellular and mitochondrial damage: e.g. deficiency of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase and deoxyguanosine kinase are associated to the most severe pathologies, the former due to an unexplained adverse effect exerted on the development and/or differentiation of dopaminergic neurons, the latter due to impairment of mitochondrial functions. This review gathers the presently known inborn errors of purine and pyrimidine metabolism that manifest neurological syndromes, reporting and commenting on the available hypothesis on the possible link between specific enzymatic alterations and brain damage. Such connection is often not obvious, and though investigated for many years, the molecular basis of most dysfunctions of central nervous system associated to purine and pyrimidine metabolism disorders are still unexplained.

show abstract

Section: Hypoxanthine-guanine Phosphoribo-syltransferase Deficiency Amentioning

confidence: 89%

Section: Hypoxanthine-guanine Phosphoribo-syltransferase Deficiency Amentioning

confidence: 91%

Neurological Disorders of Purine and Pyrimidine Metabolism

Micheli

Camici²,

Tozzi³

et al. 2011

CTMC

Self Cite

101

View full text Add to dashboard Cite

show abstract

“…A pharmacological model, the 6-hydroxydopamine-treated rat, in which catecholaminecontaining neurons were destroyed, showed self-injurious behavior in response to DOPA-agonist administration, supporting the connection between self-injurious behaviour and DA defi cit [60]. The already mentioned genetic model (the HPRT-knockout mouse) [55] did not show neurobehavioral alterations but presented an age-related decreased content of DA in the brain [61]. Various HPRT-defi cient cell cultures were developed to study the effects of the enzyme defi cit and of purine alterations [62,63,64] and confi rmed DA defi cit.…”

Section: Investigations On the Pathogenesis Of Neurological And Behavmentioning

confidence: 79%

“…By contrast decreased NAD, ATP and GTP concentrations and increased NAD production from nicotinic acid were measured in LND fi broblasts [38]. NAD concentration and related enzyme activities were found to be signifi cantly increased in liver, but not in brain or blood, of HPRT-knockout mice, animal models of LND [55]. Together these fi ndings suggested that disturbed pyridine metabolism may accompany the purine perturbation associated to HPRT defi ciency in different cell types and possibly be involved in LND neurological symptoms.…”

Section: Investigations On the Pathogenesis Of Neurological And Behavmentioning

confidence: 94%

Lesch-Nyhan disease: A rare disorder with many unresolved aspects

Micheli

Bertelli²,

Jacomelli

et al. 2018

Medical University

View full text Add to dashboard Cite

Lesch-Nyhan Disease (LND) is a rare X-linked recessive metabolic and neurological syndrome due to the defi ciency of hypoxanthine-guanine phosphoribosyltransferase (HPRT). Besides its well known "housekeeping" function this purine salvage enzyme has revealed an unexpected role in neurodevelopment, unveiled by the peculiar neurological symptoms fl anking hyperuricemia in LND: dystonia, choreoathetosis, compulsive self-injurious behaviour. Several lines of research have tried to fi nd the molecular basis for the neurological phenotype after the disease was fi rst described in 1964. Dopaminergic defi cit was then found to underlie the neurologic symptoms but the aetiology for such alteration seemed inexplicable. A number of detailed studies in the last 50 years addressed the genetic, metabolic, cognitive, behavioral and anatomical features of this disease. Initial investigations seeked for accumulation of toxic metabolites or depletion of essential molecules to disclose potential connections between purine recycling and neuronal dysfunction. In the last two decades sophisticated biotechnological methods were used for a deeper insight in the genetic and molecular aspects, unveiling a network of combined gene dysregulations in neuronal development and differentiation producing neurotransmission defects. These studies, conducted with several different approaches, allowed consistent steps forward, demonstrating transcriptional aberrations affecting different metabolic pathways in HPRT defi ciency, yet leaving many questions still unsolved.patients bearing different mutations [8,9], leading to complete or partial defi ciency. In few cases defi ciency of HPRT activity in intact cultured fi broblasts was reported not to be related to any mutation in the HPRT coding sequence but to markedly decreased HPRT expression of mRNA [10][11][12]. In these cases defi ciency was attributed to a defect in gene regulation of unknown cause. Megaloblastic anaemia unresponsive to folate therapy is also common in LND patients [13]. The basic diagnostic criterion for LND and its variants is HPRT activity assay in lysates or intact erythrocytes or fi broblasts; diagnostic suspect can be raised by grossly increased uric acid amount in plasma and urine, accompanied by increased hypoxanthine and xanthine [13].

show abstract

“…In vitro, cells tend to increase the de novo synthesis to compensate for a recycling deficit, a situation that is not physiologically possible in the brain, where the de novo pathway enzymes are only poorly active (12). This highlights the intrinsic ability of different cell types to mobilize alternative energy supplies to cope with bioenergetics stress -a property termed "metabolic flexibility" (34,35). However, 1 caveat of our study is that it mainly relied upon morphological observations of the neuronal network.…”

Section: Discussionmentioning

confidence: 99%