Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
Mov Disord. 2022 Dec;37(12):2345-2354. doi: 10.1002/mds.29211. Epub 2022 Sep 10.
Several genetic models that recapitulate neurodegenerative features of Parkinson's disease (PD) exist, which have been largely based on genes discovered in monogenic PD families. However, spontaneous genetic mutations have not been linked to the pathological hallmarks of PD in non-human vertebrates.
To describe the genetic and pathological findings of three Yellow-crowned parrot (Amazona ochrocepahala) siblings with a severe and rapidly progressive neurological phenotype.
The phenotype of the three parrots included severe ataxia, rigidity, and tremor, while their parents were phenotypically normal. Tests to identify avian viral infections and brain imaging studies were all negative. Due to their severe impairment, they were all euthanized at age 3 months and their brains underwent neuropathological examination and proteasome activity assays. Whole genome sequencing (WGS) was performed on the three affected parrots and their parents.
The brains of affected parrots exhibited neuronal loss, spongiosis, and widespread Lewy body-like inclusions in many regions including the midbrain, basal ganglia, and neocortex. Proteasome activity was significantly reduced in these animals compared to a control (P < 0.05). WGS identified a single homozygous missense mutation (p.V559L) in a highly conserved amino acid within the pleckstrin homology (PH) domain of the calcium-dependent secretion activator 2 (CADPS2) gene.
Our data suggest that a homozygous mutation in the CADPS2 gene causes a severe neurodegenerative phenotype with Lewy body-like pathology in parrots. Although CADPS2 variants have not been reported to cause PD, further investigation of the gene might provide important insights into the pathophysiology of Lewy body disorders. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
有几种能够重现帕金森病（PD）神经退行性特征的遗传模型，这些模型主要基于单基因 PD 家族中发现的基因。然而，自发性遗传突变与非人类脊椎动物 PD 的病理标志没有联系。
描述三只黄冠鹦鹉（Amazona ochrocepahala）兄妹的遗传和病理发现，它们具有严重且快速进展的神经表型。
这三只鹦鹉的表型包括严重的共济失调、僵硬和震颤，而它们的父母表型正常。检测鸟类病毒感染和脑部成像研究均为阴性。由于它们严重受损，它们在 3 个月大时被安乐死，其大脑接受了神经病理学检查和蛋白酶体活性检测。对三只受影响的鹦鹉及其父母进行了全基因组测序（WGS）。
受影响鹦鹉的大脑表现出神经元丧失、海绵状变性和广泛的路易体样包涵体，分布于中脑、基底神经节和新皮质等多个区域。与对照组相比，这些动物的蛋白酶体活性显著降低（P < 0.05）。WGS 发现钙依赖性分泌激活物 2（CADPS2）基因高度保守的 PH 结构域内的单个纯合错义突变（p.V559L）。
我们的数据表明，CADPS2 基因的纯合突变导致鹦鹉出现严重的神经退行性表型和路易体样病理学。尽管 CADPS2 变异尚未被报道可引起 PD，但对该基因的进一步研究可能为路易体疾病的病理生理学提供重要见解。© 2022 作者。运动障碍由 Wiley 期刊出版公司代表国际帕金森和运动障碍协会出版。本文已由美国政府雇员做出贡献，其工作在美国属于公有领域。
