Hopwood Centre for Neurobiology (HCN), South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
Department of Paediatrics, University of Adelaide, Adelaide, SA, Australia.
Neuropathol Appl Neurobiol. 2019 Dec;45(7):715-731. doi: 10.1111/nan.12548. Epub 2019 Apr 25.
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.
We have crossed congenic MPS IIIA mice with α-synuclein-deficient (Snca /J) mice and evaluated phenotype and brain disease lesions.
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.
黏多糖贮积症 IIIA 型（Sanfilippo 综合征；MPS IIIA）是一种遗传性儿童发病的神经退行性疾病，由溶酶体磺酰胺酶缺乏引起，随后硫酸乙酰肝素积累。导致临床疾病的病理机制尚不清楚；然而，α-突触核蛋白、磷酸化 tau 和淀粉样前体蛋白等易聚集蛋白在神经元内的积累表明细胞内运输和溶酶体降解效率低下。
研究积累的α-突触核蛋白在早期症状出现（即认知障碍、焦虑减少和运动缺陷，最早可在 3-5 个月龄时检测到）中的作用。
我们将同源性 MPS IIIA 小鼠与α-突触核蛋白缺陷（Snca /J）小鼠杂交，并评估表型和脑疾病病变。
在对 12-22 周龄小鼠进行的一系列行为测试中，我们无法区分α-突触核蛋白缺陷型 MPS IIIA 小鼠与携带一个或两个α-突触核蛋白基因的小鼠；与野生型同窝小鼠相比，所有三种受影响的基因型在测试表现中均显著受损。组织学研究显示，α-突触核蛋白缺陷型 MPS IIIA 小鼠脑内其他蛋白性病变的沉积速度、位置和性质、内溶酶体蛋白表达的中断以及炎症反应与 MPS IIIA 小鼠同型或杂合子中所见相似。
α-突触核蛋白的缺失和/或缺乏并不影响 MPS IIIA 小鼠的临床和神经病理学疾病进展，表明该蛋白本身不会引发 MPS IIIA 小鼠生命前 5 个月出现的认知和运动症状。
