Sakunthala Arunima, Maji Samir K
Sunita Sanghi Centre of Aging and Neurodegenerative Diseases (SCAN), Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
Department of Biosciences& Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
Biochemistry. 2025 Jan 21;64(2):377-400. doi: 10.1021/acs.biochem.4c00667. Epub 2025 Jan 6.
Aggregation of α-synuclein (α-Syn) and Lewy body (LB) formation are the key pathological events implicated in Parkinson's disease (PD) that spread in a prion-like manner. However, biophysical and structural characteristics of toxic α-Syn species and molecular events that drive early events in the propagation of α-Syn amyloids in a prion-like manner remain elusive. We used a neuronal cell model to demonstrate the size-dependent native biological activities of α-Syn fibril seeds. Biophysical characterization of the fibril seeds generated by controlled fragmentation indicated that increased fragmentation leads to a reduction in fibril size, correlating directly with the extent of fragmentation events. Although the size-based complexity of amyloid fibrils modulates their biological activities and fibril amplification pathways, it remains unclear how the variability of fibril seed size dictates its specific uptake mechanism into the cells. The present study elucidates the mechanism of α-Syn fibril internalization and how it is regulated by the size of fibril seeds. Further, we demonstrate that size-dependent endocytic pathways (dynamin-dependent clathrin/caveolin-mediated) are more prominent for the differential uptake of short fibril seeds compared to their longer counterparts. This size-dependent preference might contribute to the enhanced uptake and transcellular propagation of short α-Syn fibril seeds in a prion-like manner. Overall, the present study suggests that the physical dimension of α-Syn amyloid fibril seeds significantly influences their cellular uptake and pathological responses in the initiation and progression of PD.
α-突触核蛋白（α-Syn）的聚集和路易小体（LB）的形成是帕金森病（PD）中涉及的关键病理事件，它们以朊病毒样的方式传播。然而，有毒α-Syn物种的生物物理和结构特征以及以朊病毒样方式驱动α-Syn淀粉样蛋白传播早期事件的分子事件仍然难以捉摸。我们使用神经元细胞模型来证明α-Syn原纤维种子的大小依赖性天然生物学活性。通过控制片段化产生的原纤维种子的生物物理表征表明，片段化增加导致原纤维尺寸减小，这与片段化事件的程度直接相关。尽管淀粉样原纤维基于大小的复杂性调节其生物学活性和原纤维扩增途径，但尚不清楚原纤维种子大小的变异性如何决定其进入细胞的特定摄取机制。本研究阐明了α-Syn原纤维内化的机制及其如何受原纤维种子大小的调节。此外，我们证明，与较长的原纤维种子相比，大小依赖性内吞途径（依赖发动蛋白的网格蛋白/小窝蛋白介导）在短原纤维种子的差异摄取中更为突出。这种大小依赖性偏好可能有助于短α-Syn原纤维种子以朊病毒样方式增强摄取和跨细胞传播。总体而言，本研究表明，α-Syn淀粉样原纤维种子的物理尺寸在PD的起始和进展中显著影响其细胞摄取和病理反应。
