The Amyloid Inhibitor CLR01 Relieves Autophagy and Ameliorates Neuropathology in a Severe Lysosomal Storage Disease.,Molecular Therapy

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The Amyloid Inhibitor CLR01 Relieves Autophagy and Ameliorates Neuropathology in a Severe Lysosomal Storage Disease.
Molecular Therapy ( IF 12.1 ) Pub Date : 2020-02-12 , DOI: 10.1016/j.ymthe.2020.02.005
Antonio Monaco ₁ , Veronica Maffia ₁ , Nicolina Cristina Sorrentino ₁ , Irene Sambri ₁ , Yulia Ezhova ₁ , Teresa Giuliano ₁ , Vincenzo Cacace ₁ , Edoardo Nusco ₁ , Maria De Risi ₂ , Elvira De Leonibus ₂ , Thomas Schrader ₃ , Frank-Gerrit Klärner ₃ , Gal Bitan ₄ , Alessandro Fraldi ₅

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Lysosomal storage diseases (LSDs) are inherited disorders caused by lysosomal deficiencies and characterized by dysfunction of the autophagy-lysosomal pathway (ALP) often associated with neurodegeneration. No cure is currently available to treat neuropathology in LSDs. By studying a mouse model of mucopolysaccharidosis (MPS) type IIIA, one of the most common and severe forms of LSDs, we found that multiple amyloid proteins including α-synuclein, prion protein (PrP), Tau, and amyloid β progressively aggregate in the brain. The amyloid deposits mostly build up in neuronal cell bodies concomitantly with neurodegeneration. Treating MPS-IIIA mice with CLR01, a "molecular tweezer" that acts as a broad-spectrum inhibitor of amyloid protein self-assembly reduced lysosomal enlargement and re-activates autophagy flux. Restoration of the ALP was associated with reduced neuroinflammation and amelioration of memory deficits. Together, these data provide evidence that brain deposition of amyloid proteins plays a gain of neurotoxic function in a severe LSD by affecting the ALP and identify CLR01 as new potent drug candidate for MPS-IIIA and likely for other LSDs.

中文翻译：

淀粉样蛋白抑制剂 CLR01 可缓解严重溶酶体贮积病的自噬并改善神经病理学。

溶酶体贮积病 (LSD) 是由溶酶体缺陷引起的遗传性疾病，其特征是自噬-溶酶体途径 (ALP) 功能障碍，通常与神经退行性变相关。目前尚无治疗 LSD 神经病理学的方法。通过研究粘多糖贮积症 (MPS) IIIA 型小鼠模型，这是 LSD 最常见和最严重的形式之一，我们发现多种淀粉样蛋白，包括 α-突触核蛋白、朊病毒蛋白 (PrP)、Tau 和淀粉样蛋白 β 在 LSD 中逐渐聚集。脑。淀粉样蛋白沉积物主要在神经元细胞体中积聚，同时伴随着神经退行性变。用 CLR01 治疗 MPS-IIIA 小鼠，CLR01 是一种“分子镊子”，可作为淀粉样蛋白自组装的广谱抑制剂减少溶酶体增大并重新激活自噬通量。ALP 的恢复与减少神经炎症和改善记忆缺陷有关。总之，这些数据提供了证据，表明淀粉样蛋白的脑沉积通过影响 ALP 并确定 CLR01 是 MPS-IIIA 和其他 LSD 的新有效候选药物，从而在严重 LSD 中发挥神经毒性功能。

更新日期：2020-02-12

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