Relationship between Plasma Ammonia Concentration and β-N-Acetylhexosaminidase Isoenzyme Activities in Liver Cirrhosis

Pérez, Luis Francisco; Casal, J.; Rojas, Pamela; Tutor, J. Carlos

doi:10.1515/cclm.2000.195

Cited by 7 publications

(3 citation statements)

References 19 publications

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“…Indeed, although scantly investigated, some investigators reported increased ganglioside levels in ALS including GM2 ganglioside 142 , 173 , 174 . In line with ammonia’s role in ganglioside metabolism, Perez et al showed that ammonia causes leakage of Hexosaminidase A (Hex A), indicating GM2 accumulation 175 , 176 . Thus, ammonia-induced GM2 accumulation could partly explains the heightened vulnerability of motor neurons in ALS ( Figure 2 ).…”

Section: Impaired Lysosomal Ganglioside Clearancementioning

confidence: 95%

A(a)LS: Ammonia-induced amyotrophic lateral sclerosis

Parekh

2015

F1000Res

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Amyotrophic lateral sclerosis (ALS) is a dreadful, devastating and incurable motor neuron disease. Aetiologically, it is a multigenic, multifactorial and multiorgan disease. Despite intense research, ALS pathology remains unexplained. Following extensive literature review, this paper posits a new integrative explanation. This framework proposes that ammonia neurotoxicity is a main player in ALS pathogenesis. According to this explanation, a combination of impaired ammonia removal— mainly because of impaired hepatic urea cycle dysfunction—and increased ammoniagenesis— mainly because of impaired glycolytic metabolism in fast twitch skeletal muscle—causes chronic hyperammonia in ALS. In the absence of neuroprotective calcium binding proteins (calbindin, calreticulin and parvalbumin), elevated ammonia—a neurotoxin—damages motor neurons. Ammonia-induced motor neuron damage occurs through multiple mechanisms such as macroautophagy-endolysosomal impairment, endoplasmic reticulum (ER) stress, CDK5 activation, oxidative/nitrosative stress, neuronal hyperexcitability and neuroinflammation. Furthermore, the regional pattern of calcium binding proteins’ loss, owing to either ER stress and/or impaired oxidative metabolism, determines clinical variability of ALS. Most importantly, this new framework can be generalised to explain other neurodegenerative disorders such as Huntington’s disease and Parkinsonism.

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Section: Impaired Lysosomal Ganglioside Clearancementioning

confidence: 95%

A(a)LS: Ammonia-induced amyotrophic lateral sclerosis

Parekh

2015

F1000Res

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“…Indeed, although scantly investigated, some investigators reported increased ganglioside levels in ALS including GM2 ganglioside [136,166,167]. In line with ammonia's role in ganglioside metabolism, Perez et al showed that ammonia causes leakage of Hexosaminidase A (Hex A), indicating GM2 accumulation [168,169]. Thus, ammonia-induced GM2 accumulation could partly explains the heightened vulnerability of motor neurons in ALS (fig 2).…”

Section: Impaired Lysosomal Ganglioside Clearancementioning

confidence: 99%

A(a)LS: Ammonia-induced amyotrophic lateral sclerosis

Parekh

2015

Preprint

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Amyotrophic lateral sclerosis (ALS) is a dreadful, devastating and incurable motor neuron disease. Aetiologically, it is a multigenic, multifactorial and multiorgan disease. Despite intense research, ALS pathology remains unexplained. After the literature review, this paper posits a new integrative explanation. This framework proposes that ammonia neurotoxicity is a main player in ALS pathogenesis. According to this explanation, a combination of impaired ammonia removal— mainly because of impaired hepatic urea cycle dysfunction—and increased ammoniagenesis— mainly because of impaired glycolytic metabolism in fast twitch skeletal muscle—causes chronic hyperammonia in ALS. In the absence of neuroprotective calcium binding proteins (calbindin, calreticulin and parvalbumin), elevated ammonia—a neurotoxin—damages motor neurons. Ammonia-induced motor neuron damage occurs through multiple mechanisms such as macroautophagy-endolysosomal impairment, ER-stress, CDK5 activation, oxidative/nitrosative stress and neuroinflammation. Furthermore, the regional pattern of calcium binding proteins’ loss, owing to either ER stress and/or impaired oxidative metabolism, determines clinical viabilities of ALS. Most importantly, this new framework can be generalised to explain other neurodegenerative disorders such as Huntington’s disease.

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“…It is also important to note that the isoenzymatic profile of serum Hex may be modified in different physiopathological situations (30,31). In GM2 gangliosidosis, a relation has been found between the residual activity of Hex A and the severity of the disease (1), and the less severe phenotype of the B1 variant may be explained by the presence of a defective allele retaining an in vivo residual activity against the ganglioside GM2 (1,7).…”

Section: R178h Homozygote Controlsmentioning

confidence: 99%

Biochemical characterization of the GM2 gangliosidosis B1 variant

Tutor

2004

Braz J Med Biol Res

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The deficiency of the A isoenzyme of ß-hexosaminidase (Hex) produced by different mutations of the gene that codes for the α subunit (Tay-Sachs disease) has two variants with enzymological differences: the B variant consists of the absence of Hex A isoenzyme and the B1 variant produces an inactive Hex A isoenzyme for the hydrolysis of the GM2 ganglioside and synthetic substrates with negative charge. In contrast to the early childhood form of the B variant, the B1 variant appears at a later clinical stage (3 to 7 years of age) with neurodegenerative symptoms leading to the death of the patient in the second decade of life. The most frequent mutation responsible for the GM2 gangliosidosis B1 variant is R178H, which has a widespread geographic and ethnic distribution. The highest incidence has been described in Portugal, which has been suggested as the point of origin of this mutation. Biochemical characterization of this lysosomal disease is carried out using negatively charged synthetic α subunit-specific sulfated substrates, since Hex A isoenzyme heat-inactivation assays are not applicable. However, the determination of the apparent activation energy of Hex using the neutral substrate 3,3'-dichlorophenolsulfonphthaleinyl N-acetyl-ß-D-glucosaminide, may offer a valid alternative. The presence of an α subunit in the αß heterodimer Hex A means that its activation energy (41.8 kJ/mol) is significantly lower than that of the ßß homodimer Hex B (75.1 kJ/mol); however, as mutation inactivates the α subunit, the Hex A of the B1 variant presents an activation energy that is similar to that of the Hex B isoenzyme. Correspondence

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Relationship between Plasma Ammonia Concentration and β-N-Acetylhexosaminidase Isoenzyme Activities in Liver Cirrhosis

Cited by 7 publications

References 19 publications

A(a)LS: Ammonia-induced amyotrophic lateral sclerosis

A(a)LS: Ammonia-induced amyotrophic lateral sclerosis

A(a)LS: Ammonia-induced amyotrophic lateral sclerosis

Biochemical characterization of the GM2 gangliosidosis B1 variant

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