神經退化性疾病的類普利昂機制 Prion-like mechanisms in neurodegenerative diseases.

 
出處: Nature Reviews Neuroscience, Published online 23 December 2009
作者:Bess Frost & Marc I. Diamond
摘要: Many non-infectious neurodegenerative diseases are associated with the accumulation of fibrillar proteins.
These diseases all exhibit features that are reminiscent of those of prionopathies, including phenotypic diversity and the propagation of pathology. Furthermore, emerging studies of amyloid-β, α-synuclein and tau — proteins implicated in common neurodegenerative diseases — suggest that they share key biophysical and biochemical characteristics with prions. Propagation of protein misfolding in these diseases may therefore occur through mechanisms similar to those that underlie prion pathogenesis. If this hypothesis is verified in vivo, it will suggest new therapeutic strategies to block propagation of protein misfolding throughout the brain.


許多非感染性的神經退化性疾病和纖維性蛋白的累積有關. 這些疾病均有那種普利昂病理式記憶性的特性, 包括表形的歧異與病理學上的增殖. 再者, amyloid-β, α-synuclein 和 tau-proteins 的緊急研究是和一般神經退化性病有關的, 表示它們和普利昂有相同的生物物理和生物化學特性. 這些蛋白在這些疾病的錯誤折疊可能和普利昂致病性有相同的致病機制. 如果這個假說可以in vivo 獲得証實, 那就提供了一種阻止蛋白在腦中造成錯誤折疊的增殖的新的治療策略.


圖一, 神經退化性疾病中的類普利昂機制

Intracellular protein aggregation leads to cell death. This releases protein aggregates into the extracellular space, which are subsequently taken up by and corrupt protein folding in vulnerable cells. b) As part of the normal physiological processes of a living cell, protein aggregates may be released, potentially from exosomes or through exocytosis. This results in the presence of protein aggregates in the extracellular space that may be taken up by adjacent cells. Together with the mechanism shown in a, this process might account for local propagation of misfolding. c ) Aggregates might cross synapses. Release could be due to local degeneration of a synapse, could be part of normal synaptic physiology or could be part of an exocytic process (as in b). This mechanism can explain network degeneration in neurodegenerative diseases.

細胞內蛋白聚集造成細胞死亡. 而使得蛋白聚集在細胞間隙, 接著被受害細胞吸收並腐化該細胞.  b) 身為活細胞的正常生理作用的一環, 蛋白的聚集可以經由exosome或是exocytosis被釋出. 這個結果造成蛋白在細胞間隙聚集, 而且可能被隣近細胞吸收. 與 a 的機制合起來看, 這種可能是局部蛋白錯誤折疊的增殖原因. c) 聚集會通過 synapses. 釋出的過程可能是因為局部的synapses 退化, 可能是正常的 synapses 生理作用或是 exocytosis 的一環 (如 b 所示). 這個機制可以解釋神經退化疾病的網狀退化.

圖二. 新治療方式的嘗試

 

If trans-cellular propagation of protein misfolding occurs, new strategies could supplement existing approaches to promote cell survival and block intracellular accumulation of misfolded species. As the cellular mechanisms of aggregate release and uptake are delineated, it may be possible to inhibit these events pharmacologically or genetically. Antibody-based therapies might also be expanded to target protein aggregates that are generated inside a cell and released into the extracellular space.
若是跨細胞的蛋白錯誤折疊的累積真的存在, 新的策略可以提供現有的嘗試來促進細胞存活並且阻斷錯誤折疊物的累積. 如同所述的聚集物釋出和吸收的細胞機制, 或許可以用孳物或是基因療法抑制這些情況. 抗體型式的治療可以提升為針對細胞內形成, 且會釋出到細胞間隙的蛋白聚集物而製作的.