Early disease course is unaltered in mucopolysaccharidosis type IIIA (MPS IIIA) mice lacking α‐synuclein

Abstract

2019)Neuropathology and Applied Neurobiology 45, 715-731 Early disease course is unaltered in mucopolysaccharidosis type IIIA (MPS IIIA) mice lacking a-synuclein Background: 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 a-synuclein, phosphorylated tau and amyloid precursor protein suggests inefficient intracellular trafficking and lysosomal degradation. Aim: To investigate the contribution the accumulating a-synuclein plays in early symptom emergence that is, impaired cognition, reduced anxiety and motor deficits, first detectable between 3-5 months of age. Methods: We have crossed congenic MPS IIIA mice with a-synuclein-deficient (Snca tm1Rosl /J) mice and evaluated phenotype and brain disease lesions. Results: In a battery of behavioural tests performed on mice aged 12-22 weeks, we were unable to differentiate a-synuclein-deficient MPS IIIA mice from those with one or both copies of the a-synuclein gene; all three affected genotypes were significantly impaired in test performance when compared to wildtype 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 a-synuclein-deficient MPS IIIA mice reflected that seen in MPS IIIA mice homo-or heterozygous for a-synuclein. Conclusion: Deletion and/or deficiency of a-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.

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

“…This is in line with a study by Sambri et al which demonstrated that perikaryal accumulation of insoluble α-synuclein and increased proteasomal degradation of cysteine string protein α (CSPα) led to their deficiency in the presynaptic terminal and consequently affected synaptic vesicle integrity and recycling [130]. In contrast, a recent study demonstrated that genetic depletion of α-synuclein failed to rescue or reduce cognitive and motor symptoms in an MPS IIIA mouse model [131]. Autophagic processes in these mice were not improved either, with defective macroautophagy as well as elevated numbers of phosphorylated tau and ubiquitin inclusions similar to those in congenic MPS IIIA mice.…”

“…Autophagic processes in these mice were not improved either, with defective macroautophagy as well as elevated numbers of phosphorylated tau and ubiquitin inclusions similar to those in congenic MPS IIIA mice. Thus, the accumulation of phosphorylated tau is thought to be more relevant to the development of neuropathology [131]. Taken together, these results indicate that aggregate-prone proteins linked to neurodegeneration in adult neurologic disorders such as Alzheimer's and Parkinson's disease accumulate in the MPS III brain, though the specific effects of these proteins (and their interaction) on clinical progression of the disease remain to be clarified.…”

Neurocognitive testing in a murine model of mucopolysaccharidosis type IIIA

“…1 ), concordant with previous studies [ 8 , 16 ] and reflecting human mid-stage disease cognitive skill regression and dementia [ 18 ]. To date, the water crossmaze has not been widely employed as the Morris Water Maze (MWM) has traditionally been used reporting memory and learning impairment in MPS IIIA mice as early as 4 months of age [ 12 , 27 ]. However, Fu et al (2016) [ 7 ] showed 7.5 months was the earliest age of impairment.…”

“…Behaviour studies in mice can be variable due to differences in environmental factors and equipment, animal handling and investigator interpretations, mouse housing, upbringing and prior (testing) experience [ 11 ]. For example, hypoactivity has been reported at 3–8 months of age in MPS IIIA mice [ 8 , 12 , 13 ] and hyperactivity [ 14 , 15 ] or “normal” activity has been found at 2–9 months of age [ 9 , 16 , 17 ].…”

Is SGSH heterozygosity a risk factor for early‐onset neurodegenerative disease?

“…Dopamine was quantified as per. 36 Briefly, tissues were homogenised and sonicated in 50:50 methanol: water, and 100 μL of homogenate was added to 10 μL of d 4 dopamine internal standard (1000 ng/mL); 400 μL of acetonitrile was added, and samples were vortexed for 1 minute and then cooled at −20 C for 30 minutes. Following centrifugation, the supernatant (~350 μL) was removed into a glass tube and dried down under nitrogen.…”