alpha-synuclein and Mucopolysaccharidosis-III

Sanfilippo syndrome (mucopolysaccharidosis type IIIA; MPS IIIA) is an inherited paediatric-onset neurodegenerative disorder caused by the lysosomal deficiency of sulphamidase with subsequent accumulation of heparan sulphate. The pathological mechanisms responsible for clinical disease are unknown; however, intraneuronal accumulation of aggregation-prone proteins such as α-synuclein, phosphorylated tau and amyloid precursor protein suggests inefficient intracellular trafficking and lysosomal degradation.. To investigate the contribution the accumulating α-synuclein plays in early symptom emergence that is, impaired cognition, reduced anxiety and motor deficits, first detectable between 3-5 months of age.. In a battery of behavioural tests performed on mice aged 12-22 weeks, we were unable to differentiate α-synuclein-deficient MPS IIIA mice from those with one or both copies of the α-synuclein gene; all three affected genotypes were significantly impaired in test performance when compared to wild-type littermates. Histological studies revealed that the rate, location and nature of deposition of other proteinaceous lesions, the disruption to endolysosomal protein expression and the inflammatory response seen in the brain of α-synuclein-deficient MPS IIIA mice reflected that seen in MPS IIIA mice homo- or heterozygous for α-synuclein.. Deletion and/or deficiency of α-synuclein does not influence clinical and neuropathological disease progression in murine MPS IIIA, demonstrating that in and of itself, this protein does not initiate the cognitive and motor symptoms that occur in the first 5 months of life in MPS IIIA mice.

Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Disease Progression; Mice; Mice, Knockout; Mucopolysaccharidosis III

Axonal dystrophy has been described as an early pathological feature of neurodegenerative disorders including Alzheimer's disease and amyotrophic lateral sclerosis. Axonal inclusions have also been reported to occur in several neurodegenerative lysosomal storage disorders including Mucopolysaccharidosis type IIIA (MPS IIIA; Sanfilippo syndrome). This disorder results from a mutation in the gene encoding the lysosomal sulphatase sulphamidase, and as a consequence heparan sulphate accumulates, accompanied by secondarily-stored gangliosides. The precise basis of symptom generation in MPS IIIA has not been elucidated, however axonal dystrophy may conceivably lead to impaired vesicular trafficking, neuronal dysfunction and/or death. We have utilised a faithful murine model of MPS IIIA to determine the spatio-temporal profile of neuronal inclusion formation and determine the effect of restoring normal lysosomal function. Dopaminergic (tyrosine hydroxylase-positive), cholinergic (choline acetyltransferase-positive) and GABAergic (glutamic acid decarboxylase

Topics: alpha-Synuclein; Amyloid beta-Protein Precursor; Animals; Axons; Brain; Female; Hydrolases; Immunohistochemistry; Lysosomes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucopolysaccharidosis III; tau Proteins

Parkinson's disease (PD) is a common neurodegenerative disorder of unknown etiology. The characteristic α-synuclein aggregation of PD is also a feature of Sanfilippo syndrome, a storage disorder caused by α-N-acetylglucosaminidase (NAGLU) gene mutations. We explored genetic links between these disorders and studied the pathology of Sanfilippo syndrome to investigate a common pathway toward α-synuclein aggregation.. We typed the 2 single-nucleotide polymorphisms that tag the common haplotypes of NAGLU in 926 PD patients and 2308 controls and also stained cortical tissue from 2 cases of Sanfilippo A syndrome using the anti-α-synuclein antibody, Per7.. Allelic analysis showed an association between rs2071046 and risk for PD (P 1.3 × 10(-3) ). Intracellular α-synuclein accumulation was observed in the cortical tissue of both Sanfilippo A syndrome cases.. This study suggests a possible role of NAGLU in susceptibility to PD while extending evidence for α-synuclein aggregation in the brain in lysosomal storage disorders. Our findings support a mechanism involving lysosomal dysfunction more generally in the pathogenesis of PD.

Topics: Acetylglucosaminidase; Aged; alpha-Synuclein; Cohort Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Male; Middle Aged; Mucopolysaccharidosis III; Parkinson Disease; Polymorphism, Single Nucleotide