Blood-brain barrier impairment in MPS III patients
Svitlana Garbuzova-Davis1, Santhia Mirtyl, Sebastian A Sallot
1Center of Excellence for Aging & Brain Repair, University of South Florida, Morsani College of Medicine, 12901 Bruce B, Downs Blvd, Tampa, FL 33612, USA. sgarbuzo@health.usf.edu.
Background:
Mucopolysaccharidosis type III (MPS III) is an autosomal recessive disorder caused by deficiency of a specific enzyme leading to heparan sulfate (HS) accumulation within cells and to eventual progressive cerebral and systemic organ abnormalities. Different enzyme deficiencies comprise the MPS III subcategories (A, B, C, D). Since neuropathological manifestations are common to all MPS III types, determining blood-brain barrier (BBB) condition may be critical to understand potential additional disease mechanisms.
Methods:
We investigated BBB integrity in various brain structures of post-mortem tissues from an eleven year old Caucasian female with MPS III A and from a twenty four year old Caucasian female with MPS III D. Control tissues were obtained post-mortem from three Caucasians without neurological deficits: a twelve year old male, a twenty four year old female, and a twenty seven year old female. BBB capillary ultrastructure (electron microscopy) and capillary functional integrity (IgG leakage, tight junction proteins, and lysosomal accumulation within endothelium) were examined.
Results:
Compromised BBB integrity was found in both MPS III cases. Major study findings were: (1) capillary endothelial and pericyte cell damage; (2) mucopolysaccharide bodies in a majority of endothelial cells and pericytes rupturing cell membranes; (3) severe extracellular edema; (4) IgG microvascular leakage and reductions of occludin and claudin-5 with variations between MPS III types; (5) extensive lysosomal accumulation in capillary endothelium.
Conclusions:
These new findings of BBB structural and functional impairment, although from only two cases, MPS III A and III D, may have implications for disease pathogenesis and should be considered in treatment development for MPS III.
Insights
Mucopolysaccharidosis type III (MPS III) causes brain damage due to impaired blood-brain barrier (BBB) function. This study found structural and functional BBB defects in MPS III patients, suggesting a role in disease progression and treatment strategies.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Mucopolysaccharidosis type III (MPS III) is a genetic disorder causing heparan sulfate accumulation and progressive neurological damage.
- Neuropathological features are common across MPS III subtypes (A, B, C, D).
- Understanding blood-brain barrier (BBB) integrity is crucial for MPS III pathogenesis.
Purpose of the Study:
- To investigate the structural and functional integrity of the BBB in MPS III.
- To compare BBB condition in MPS III A and MPS III D subtypes.
Main Methods:
- Post-mortem brain tissues from MPS III A and MPS III D patients were analyzed.
- Control brain tissues from neurologically healthy individuals were used for comparison.
- Methods included electron microscopy, IgG leakage assessment, tight junction protein analysis, and lysosomal accumulation evaluation.
Main Results:
- Both MPS III cases exhibited compromised BBB integrity.
- Findings included endothelial and pericyte damage, mucopolysaccharide body rupture, extracellular edema, IgG leakage, reduced tight junction proteins (occludin, claudin-5), and lysosomal accumulation.
- Variations in findings were observed between MPS III subtypes.
Conclusions:
- Structural and functional BBB impairment is evident in MPS III.
- These BBB alterations may contribute to MPS III pathogenesis.
- Consideration of BBB status is important for developing future MPS III treatments.
