Neurodegeneration-linked proteins accumulate across Sanfilippo types
Study sheds light on possible mechanisms that contribute to disease
A number of proteins that accumulate to toxic levels in other neurodegenerative diseases also build up in cells derived from patients with all types of Sanfilippo syndrome, but treating the cells with a molecule to reduce heparan sulfate, which accumulates in Sanfilippo, also caused the other protein levels to go down, a study shows.
The study’s researchers said this sheds light on possible mechanisms that contribute to Sanfilippo syndrome and shows there may be overlap in the mechanisms between Sanfilippo and other neurodegenerative diseases. The study, “Comprehensive evaluation of pathogenic protein accumulation in fibroblasts from all subtypes of Sanfilippo disease patients,” was published in Biochemical and Biophysical Research and Communications.
In Sanfilippo syndrome, also called mucopolysaccharidosis type III, the complex sugar molecule heparan sulfate builds up in cells, which leads to a pediatric form of dementia that includes behavioral problems, developmental delays, and a range of other symptoms. Each of its four disease types are caused by mutations in different genes that encode the production of enzymes normally involved in breaking down heparan sulfate.
The clinical course of these four disease types varies, however. Sanfilippo type A, which is generally considered the most severe form, is marked by early-onset and rapidly progressing disease, whereas Sanfilippo type C, which may be considered the mildest form, tends to progress more slowly.
This suggests more than heparan sulfate accumulation may influence the severity and timing of Sanfilippo progression. One possibility is the toxic accumulation of other proteins, which may form clumps, or aggregates, that impair cellular function. Such aggregation is common across a range of neurodegenerative diseases and some studies have seen evidence of it in Sanfilippo mouse models and patients.
Do other neurodegeneration proteins have a link to Sanfilippo?
Understanding the role of these proteins in Sanfilippo “might also indicate novel, potential therapeutical targets in this as yet uncurable disease,” wrote the researchers, who sought to measure the levels of other proteins in skin cells derived from patients with all subtypes of Sanfilippo. They focused on proteins that have been implicated in other neurodegenerative diseases, including alpha-synuclein, which accumulates in Parkinson’s disease, TDP43, which is seen in amyotrophic lateral sclerosis (ALS), and forms of beta-amyloid and tau, which accumulate in Alzheimer’s disease.
As expected, heparan sulfate and a related molecule called dermatan sulfate, together called glycosaminoglycans (GAGs), were found at higher levels in patient cells than in cells from healthy people. Their accumulation was lowest in Sanfilippo type C.
In general, levels of the neurodegeneration-related proteins were significantly elevated in cells derived from patients with Sanfilippo relative to cells from healthy people, although a couple weren’t increased in Sanfilippo type C.
Under a microscope, the researchers found the proteins were also forming more aggregates in the Sanfilippo cell lines than healthy cells, but, again, not all of the changes were observed in Sanfilippo type C.
When the cells were treated with genistein, a molecule that lowers GAG, levels of most of the other accumulated proteins also decreased as did the degree to which they clumped up, suggesting there are common mechanisms that lead to protein accumulation in Sanfilippo and other neurodegenerative conditions. Indeed, gene activity analyses of the cells indicated a number of genes with altered activity in the Sanfilippo cells have also been implicated in Alzheimer’s, ALS, and Parkinson’s.
Based on the findings and research in other neurodegenerative diseases, the scientists believe GAGs may be at least partially responsible for toxic protein aggregation across Sanfilippo and other conditions, possibly by regulating the activity of other neurodegeneration-related genes. The finding, which the researchers said was the first to describe “the problem of deposited protein aggregates in all subtypes of Sanfilippo disease,” helps to detail the mechanisms of the disease.
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