Ganglioside patterns in amyotrophic lateral sclerosis brain regions

Rapport, Maurice M.; Donnenfeld, Hyman; Brunner, William; Hungund, Basalingappa L.; Bartfeld, Harry

doi:10.1002/ana.410180111

Cited by 57 publications

(27 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent metabolic study by means of PET [9] showed diffuse cerebral cortical hypometabolism, suggesting extramotor neuronal func tional impairment. Studies of ganglioside pattern abnor malities also showed that the disease process in ALS extends beyond the motor cortex [12].…”

Section: Discussionmentioning

confidence: 99%

“…The concept of motor neuron disease (MND) as a dis order restricted to the motoneurons has been challenged on the basis of electrophysiological or pathological evi dence of changes in central and peripheral sensory fibers [1][2][3][4] and pathological [5][6][7][8], neuroradiological [9][10][11] and biochemical [12] verification of extramotor cerebral involvement.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Neuropsychological, Electroencephalogram and Brain Computed Tomography Findings in Motor Neuron Disease

et al. 1989

View full text Add to dashboard Cite

Thirty-five patients affected with sporadic motor neuron disease (MND) and without clinically evident mental deterioration were systematically investigated by means of neuropsychological tests, quantitative analysis of EEG and brain CT. The MND patients as a group showed a slight but definite and stereotyped cognitive impairment. Temporal slow EEG activity was increased in the whole MND group and posterior background activity was slower in the more cognitively impaired patients. No significant differences were found in CT measurements of brain atrophy between MND and controls.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuropsychological, Electroencephalogram and Brain Computed Tomography Findings in Motor Neuron Disease

et al. 1989

View full text Add to dashboard Cite

show abstract

“…Evidence includes the detection of unique gangliosides (10), high titer serum auto-antibodies to GM2 and GM1 (11,12), and elevated GM2 levels within the motor cortex of ALS patients (13). Furthermore, a number of neuromuscular diseases are associated with mutations in genes that regulate the metabolism of Cer and GSLs.…”

mentioning

confidence: 99%

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Dodge

Treleaven

Pacheco

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

141

View full text Add to dashboard Cite

Recent genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases including hereditary spastic paraplegia, hereditary sensory neuropathy type 1, and non-5q spinal muscular atrophy. Here, we investigated whether altered glycosphingolipid metabolism is a modulator of disease course in amyotrophic lateral sclerosis (ALS). Levels of ceramide, glucosylceramide, galactocerebroside, lactosylceramide, globotriaosylceramide, and the gangliosides GM3 and GM1 were significantly elevated in spinal cords of ALS patients. Moreover, enzyme activities (glucocerebrosidase-1, glucocerebrosidase-2, hexosaminidase, galactosylceramidase, α-galactosidase, and β-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1 G93A mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1 G93A mice, whereas infusion of exogenous GM3 significantly slowed the onset of paralysis and increased survival. Our results suggest that glycosphingolipids are likely important participants in pathogenesis of ALS and merit further analysis as potential drug targets.A myotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective loss of motor neurons (MNs) within the CNS. Although our understanding of the genetic basis of ALS has advanced greatly in recent years (1), the adverse biological processes that converge on the neuromuscular axis to drive both MN death and neuropathological features in additional cell types remain largely unknown. Glycosphingolipids (GSLs) are a heterogeneous group of membrane lipids formed through the covalent linkage of a glycan moiety to ceramide (Cer; see SI Appendix, Fig. S1 for an overview of GSL metabolism). Glucosylceramide (GlcCer) and galactosylceramide (GalCer) are GSLs with a single sugar residue: glucose and galactose respectively. The successive addition of galactose and sialic acid moieties to GlcCer results in the synthesis of gangliosides (e.g., GM3, GM2, and GM1) (2). GSLs are especially abundant in the CNS and have bioactive roles in metabolism, growth factor signaling, oligodendrocyte differentiation, neuroinflammation, angiogenesis, and pathways of cell death (2-9)-all of which are thought to participate in ALS disease pathogenesis.Several lines of evidence suggest that aberrant changes in GSL homeostasis may contribute to disease pathogenesis in ALS. Evidence includes the detection of unique gangliosides (10), high titer serum auto-antibodies to GM2 and GM1 (11,12), and elevated GM2 levels within the motor cortex of ALS patients (13). Furthermore, a number of neuromuscular diseases are associated with mutations in genes that regulate the metabolism of Cer and GSLs. For example, hereditary sensory neuropathy type I (HSNT1), a disease that features dorsal root ganglion cell and MN degeneration, is attributed to mutations in serine...

show abstract

“…There is, however, considerable discrepancy between clinical signs and extent and degree of pathological involvement [lo, 12, 21, 22, 291. This is especially noticeable in the motor and associated motor cortex where histological changes may be unremarkable, even in the presence of clinically severe UMN involvement [G, 10,11,25,291. In addition, it is not certain whether atrophy precedes loss in affected neurons.…”

mentioning

confidence: 99%

Lowered cerebral glucose utilization in amyotrophic lateral sclerosis

Dalakas

Hatazawa

Brooks

et al. 1987

Annals of Neurology

155

View full text Add to dashboard Cite

Regional cerebral metabolic rates for glucose (rCMRGlc) were analyzed in 19 studies of 12 patients with amyotrophic lateral sclerosis (ALS) by positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-D-glucose. In the 8 ALS patients with upper motor neuron signs, the mean cortical rCMRGlc was significantly lower than in 11 age-matched control subjects (p less than 0.01). The degree of hypometabolism correlated with the duration of the clinical signs and extended throughout the cortex and basal ganglia, but not to the cerebellum. Of the 4 such patients who had repeat PET scans, 3 demonstrated significant subsequent reduction in the rCMRGlc, corresponding to the worsening of the clinical picture. In contrast, 4 ALS patients with disease confined to lower motor neurons and 3 patients with lower motor neuron disease from old paralytic poliomyelitis had normal or near-normal rCMRGlc throughout the brain. Because histological evidence shows no generalized neuronal cell loss in the cortex of ALS patients, including in some cases the primary motor regions, the demonstration of severe generalized hypometabolism in structurally normal cortex indicates that some cortical neurons exist in a state of neuronal nonfunction, rather than cell death, and that anatomoclinical correlations may be more complex. The data also indicate that ALS with upper motor neuron involvement extends beyond the corticospinal tracts and differs in cortical function from the ALS confined to lower motor neurons or the other lower motor neuron disorders.

show abstract

Ganglioside patterns in amyotrophic lateral sclerosis brain regions

Cited by 57 publications

References 11 publications

Neuropsychological, Electroencephalogram and Brain Computed Tomography Findings in Motor Neuron Disease

Neuropsychological, Electroencephalogram and Brain Computed Tomography Findings in Motor Neuron Disease

Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis

Lowered cerebral glucose utilization in amyotrophic lateral sclerosis

Contact Info

Product

Resources

About