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Dolichol and dolichyl phosphate in the neuronal ceroid-lipofuscinoses and other diseases
L S Wolfe1, S Gauthier, M Haltia
1Donner Laboratory of Experimental Neurochemistry, Montreal Neurological Institute and Hospital, Quebec, Canada.
Insights
Neuronal ceroid lipofuscinosis (NCL) and other lysosomal storage diseases show a significant increase in dolichyl phosphates in the brain. This suggests impaired dolichyl phosphate metabolism in these conditions.
Area of Science:
- Biochemistry
- Neuroscience
- Cell Biology
Background:
- Neuronal ceroid lipofuscinosis (NCL) involves progressive neurodegeneration.
- Dolichols and dolichyl phosphates are key components of the N-glycosylation pathway.
- Altered lipid metabolism is implicated in various neurodegenerative disorders.
Purpose of the Study:
- To investigate the levels and proportions of dolichols and dolichyl phosphates in the brain and other organs of patients with NCL and related lysosomal storage diseases.
- To compare these levels with those in age-matched controls and patients with Alzheimer disease.
- To explore the potential implications of these findings for understanding disease mechanisms.
Main Methods:
- Biochemical analysis of dolichol and dolichyl phosphate levels in post-mortem brain tissue (cerebral cortex, temporal cortex), liver, kidney, and heart samples.
- Comparison of lipid profiles between patients with NCL, GM1-gangliosidosis, Tay-Sachs disease, Alzheimer disease, and age-matched controls.
Main Results:
- Nonphosphorylated dolichols and dolichyl phosphates are significantly elevated in the cerebral cortex of NCL patients.
- Dolichyl phosphates constitute a much higher proportion (59-85%) of total dolichols in NCL brains compared to controls (18-36%).
- Similar proportional increases in dolichyl phosphates are observed in GM1-gangliosidosis and Tay-Sachs disease brains, and in the kidney and heart of NCL patients.
- Elevated dolichols and dolichyl phosphates are also found in the temporal cortex of Alzheimer disease patients, though to a lesser extent than in NCL.
Conclusions:
- The marked increase in dolichyl phosphates in NCL and other lysosomal storage diseases suggests a defect in their catabolism.
- Lysosomal storage may lead to impaired dolichyl phosphate breakdown within Golgi saccules or primary lysosomes.
- These findings highlight a potential role for altered dolichol metabolism in the pathogenesis of NCL and related neurodegenerative conditions.
Abstract:
Although, compared to age-matched control samples, nonphosphorylated dolichols are significantly increased in the cerebral cortex of children with the late infantile and juvenile types of neuronal ceroid-lipofuscinosis (NCL), dolichyl phosphates are increased to a much greater extent in infantile, late infantile, and juvenile forms of this disease group. Dolichyl phosphates in the cerebral cortex, expressed as a percentage of the combined nonphosphorylated and phosphorylated compounds, ranged from 59 to 85 (mean 71) in NCL, whereas in the non-NCL disease group the range is 18-36 (mean 25). This marked proportional increase in dolichyl phosphates is not unique to NCL but is also found in the brain of GM1-gangliosidosis and Tay-Sachs disease patients. In the liver from NCL patients, dolichyl phosphates are not a major proportion of the total dolichol compounds (1-9%). However, in the kidney and heart, dolichyl phosphates are again markedly increased, and this is associated with large storage of ceroid. Although to a lesser extent than in NCL, dolichols and dolichyl phosphates are significantly increased over levels in age-matched control samples in the temporal cortex in Alzheimer disease. Our interpretation of these results is that storage in secondary in secondary lysosomes in NCL and the gangliosidoses leads to a decrease in the catabolism of dolichyl phosphate compounds in the Golgi saccules or primary lysosomes.