González-Lizárraga Florencia, Boluda Susana, Hidalgo José Ruiz, Avila Cesar L, Santos Camille Dos, Socias Benjamin, Medina Luciana, Chaumont Hugo, Akbar David, Roze Emmanuel, Chehin Rosana, Raisman-Vozari Rita, Michel Patrick Pierre, Lannuzel Annie
IMMCA, CONICET-UNT-SIPROSA, San Miguel de Tucumán, Tucumán, Argentina.
Paris Brain Institute-ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, Sorbonne Université, Paris, France.
Neuropathol Appl Neurobiol. 2025 Aug;51(4):e70026. doi: 10.1111/nan.70026.
There is an unexpectedly high proportion of atypical forms of degenerative parkinsonism in the French Caribbean islands. Residents of these islands are thought to be susceptible to Caribbean atypical parkinsonism (CAP) owing to their consumption of Annonaceae plant products containing the mitochondrial toxin annonacin. Here, we aimed to better correlate the clinical diagnosis of CAP with the misfolded protein pathology observed in affected individuals and to further investigate how annonacin could contribute to CAP pathogenesis.
We conducted postmortem histopathological analysis of brain samples from eight patients; more specifically, we assessed the distribution and burden of α-synuclein (αS) and tau pathologies. Additionally, we studied how annonacin influences αS and tau aggregation using biophysical assays, with the corresponding recombinant human proteins serving as substrates.
CAP was associated with heterogeneous clinical and histopathological features. Tau/αS copathology with a predominance of either αS or tau aggregates was observed in the majority (5/8) of patients. Tau and αS aggregates were sometimes colocalised in the same brain regions or cells. In biophysical assays, we showed that annonacin leads to an increase in αS aggregation and the formation of αS fibrils that could cross-seed tau aggregation.
Annonacin may contribute to degenerative CAP by modulating the production of tau and αS pathogenic protein assemblies.
在法属加勒比群岛，非典型形式的退行性帕金森病比例出奇地高。这些岛屿的居民被认为易患加勒比非典型帕金森病（CAP），因为他们食用了含有线粒体毒素番荔枝宁的番荔枝科植物产品。在此，我们旨在更好地将CAP的临床诊断与受影响个体中观察到的错误折叠蛋白病理学相关联，并进一步研究番荔枝宁如何导致CAP发病机制。
我们对8名患者的脑样本进行了尸检组织病理学分析；更具体地说，我们评估了α-突触核蛋白（αS）和tau病理学的分布和负担。此外，我们使用生物物理测定法研究了番荔枝宁如何影响αS和tau聚集，相应的重组人蛋白作为底物。
CAP与异质性临床和组织病理学特征相关。在大多数（5/8）患者中观察到以αS或tau聚集体为主的tau/αS共病理学。tau和αS聚集体有时在同一脑区或细胞中共定位。在生物物理测定中，我们表明番荔枝宁导致αS聚集增加和αS纤维形成，后者可交叉引发tau聚集。
番荔枝宁可能通过调节tau和αS致病蛋白聚集体的产生来导致退行性CAP。
