Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy

Abstract

Sanfilippo syndrome type B (mucopolysaccharidosis III B, MPS III B)is an autosomal recessive, neurodegenerative disease of children, characterized by profound mental retardation and dementia. The primary cause is mutation in the NAGLU gene, resulting in deficiency of ␣-N-acetylglucosaminidase and lysosomal accumulation of heparan sulfate. In the mouse model of MPS III B, neurons and microglia display the characteristic vacuolation of lysosomal storage of undegraded substrate, but neurons in the medial entorhinal cortex (MEC) display accumulation of several additional substances. We used whole genome microarray analysis to examine differential gene expression in MEC neurons isolated by laser capture microdissection from Naglu ؊/؊ and Naglu ؉/؊ mice. Neurons from the lateral entorhinal cortex (LEC) were used as tissue controls. The highest increase in gene expression (6-to 7-fold between mutant and control) in MEC and LEC neurons was that of Lyzs, which encodes lysozyme, but accumulation of lysozyme protein was seen in MEC neurons only. Because of a report that lysozyme induced the formation of hyperphosphorylated tau (Ptau) in cultured neurons, we searched for P-tau by immunohistochemistry. P-tau was found in MEC of Naglu ؊/؊ mice, in the same neurons as lysozyme. In older mutant mice, it was also seen in the dentate gyrus, an area important for memory. Electron microscopy of dentate gyrus neurons showed cytoplasmic inclusions of paired helical filaments, P-tau aggregates characteristic of tauopathies-a group of age-related dementias that include Alzheimer disease. Our findings indicate that the Sanfilippo syndrome type B should also be considered a tauopathy.hyperphosphorylated tau ͉ lysozyme ͉ mucopolysaccharidosis ͉ entorhinal cortex ͉ gene expression microarray

Plasma Signature of Neurological Disease in the Monogenetic Disorder Niemann-Pick Type C

“…Lysozyme at higher concentration has been shown to be amyloidogenic (51), and exposure of cultured rat neurons to oligomers of hen egg white lysozyme has been found to induce hyperphosphorylation of tau (52). In fact, neurons expressing lysozyme have been shown to have increased hyperphosphorylated tau in the mucopolysaccharidosis type IIIB mouse brain (28). Therefore, it is plausible that overexpression of lysozyme may allow it to reach a critical concentration at which it either oligomerizes or aggregates and serves as a template for the aggregation of tau and its phosphorylation in the cerebellum.…”

Interaction Between Eye Pigment Genes and Tau-Induced Neurodegeneration inDrosophila melanogaster

“…Granules with improper pigment balance due to white, brown, or scarlet mutations become autolysosomes (Shoup 1966;Stark and Sapp 1988). Lysosomal dysregulation is a characteristic feature of Niemann-Pick disease type C and Sanfillipo syndrome type B, both tauopathies Sokol et al 1988;Suzuki et al 1995;Ohmi et al 2009). Additionally, Dermaut et al (2005) showed that abnormal loss-of-function mutations in benchwarmer, which are associated with enlarged lysosomes, also dose dependently enhance tau toxicity.…”

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

“…1,3 While detailed mechanisms of pathology, especially the neuropathology of MPS III, are not yet well understood, numerous studies have reported cascades of complex secondary pathological events in the CNS, including broad metabolic impairments, [4][5][6] neuroinflammation, 5,7-11 oxidative stress, 10,12 autophagy, 13,14 and neurodegeneration. 7,9,11,[15][16][17][18][19][20] It is worth noting that many of these secondary neuropathological features of MPS IIIB, such as b-amyloid (Ab) aggregation, 15,18 tauopathy, 17,18 synucleinopathy, 16,19 oxidative stress, 10,12 and neuroimflammation, 5,[7][8][9][10][11] are also common hallmarks of other neurodegenerative diseases like Alzheimer's (AD) 21,22 and Parkinson's disease (PD). 23,24 In addition, our recent studies demonstrate widespread profound neuropathology in the peripheral nervous system (PNS), 25 indicating that neuropathological manifestation affects the entire nervous system.…”