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Spinal manifestations of CLN1 disease start during the early postnatal period
Neuropathology and Applied Neurobiology ( IF 5 ) Pub Date : 2020-09-07 , DOI: 10.1111/nan.12658
H R Nelvagal 1 , J T Dearborn 2 , J R Ostergaard 3 , M S Sands 2, 4 , J D Cooper 1, 4, 5
Affiliation  

AIM To understand the progression of CLN1 disease and develop effective therapies we need to characterise early sites of pathology. Therefore, we performed a comprehensive evaluation of the nature and timing of early CLN1 disease pathology in the spinal cord, which appears especially vulnerable, and how this may affect behaviour. METHODS We measured the spinal volume and neuronal number, and quantified glial activation, lymphocyte infiltration and oligodendrocyte maturation, as well as cytokine profile analysis during the early stages of pathology in Ppt1-deficient (Ppt1-/- ) mouse spinal cords. We then performed quantitative gait analysis and open-field behaviour tests to investigate the behavioural correlates during this period. RESULTS We detected significant microglial activation in Ppt1-/- spinal cords at 1 month. This was followed by astrocytosis, selective interneuron loss, altered spinal volumes and oligodendrocyte maturation at 2 months, before significant storage material accumulation and lymphocyte infiltration at 3 months. The same time course was apparent for inflammatory cytokine expression that was altered as early as one month. There was a transient early period at 2 months when Ppt1-/- mice had a significantly altered gait that resembles the presentation in children with CLN1 disease. This occurred before an anticipated decline in overall locomotor performance across all ages. CONCLUSION These data reveal disease onset two months (25% of life-span) earlier than expected, while spinal maturation is still ongoing. Our multi-disciplinary data provide new insights into the spatio-temporal staging of CLN1 pathogenesis during ongoing postnatal maturation, and highlight the need to deliver therapies during the pre-symptomatic period.

中文翻译:

CLN1 疾病的脊柱表现始于产后早期

目的为了了解 CLN1 疾病的进展并开发有效的治疗方法,我们需要表征早期病理部位。因此,我们对脊髓中早期 CLN1 疾病病理学的性质和时间进行了全面评估,这似乎特别脆弱,以及这可能如何影响行为。方法我们测量了脊髓体积和神经元数量,并量化了 Ppt1 缺陷 (Ppt1-/-) 小鼠脊髓病理早期阶段的神经胶质激活、淋巴细胞浸润和少突胶质细胞成熟,以及细胞因子谱分析。然后,我们进行了定量步态分析和开放场行为测试,以调查此期间的行为相关性。结果 我们在 1 个月时检测到 Ppt1-/- 脊髓中显着的小胶质细胞激活。随后是星形细胞增多症、选择性中间神经元丢失、脊髓体积改变和少突胶质细胞在 2 个月时成熟,然后在 3 个月时出现显着的储存材料积累和淋巴细胞浸润。炎症细胞因子的表达在同一时间过程中很明显,早在 1 个月就发生了改变。当 Ppt1-/- 小鼠的步态显着改变时,在 2 个月时有一个短暂的早期阶段,类似于患有 CLN1 疾病的儿童的表现。这发生在所有年龄段的整体运动能力预期下降之前。结论 这些数据显示疾病发作比预期早两个月(寿命的 25%),而脊柱成熟仍在进行中。
更新日期:2020-09-07
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