Phospholipase A2G6-associated neurodegeneration (PLAN) is a rare early-onset monogenic neurodegenerative movement disorder which targets the basal ganglia and other regions in the central and peripheral nervous system; presenting as a series of heterogenous subtypes in patients. We describe here a B6.C3-Pla2g6^m1J/CxRwb mouse model of PLAN which presents with early-onset neurodegeneration at 90 days which is analogous of the disease progression that is observed in PLAN patients. Homozygous mice had a progressively worsening motor deficit, which presented as tremors starting at 65 days and progressed to severe motor dysfunction and increased falls on the wire hang test at 90 days. This motor deficit positively correlated with a reduction in tyrosine hydroxylase (TH) protein expression in dopaminergic neurons of the substantia nigra (SN) without any neuronal loss. Fluorescence imaging of Thy1-YFP revealed spheroid formation in the SN. The spheroids in homozygous mice strongly mirrors those observed in patients and were demonstrated to correlate strongly with the motor deficits as measured by the wire hang test. The appearance of spheroids preceded TH loss and increased spheroid numbers negatively correlated with TH expression. Perls/DAB staining revealed the presence of iron accumulation within the SN of mice. This mouse model captures many of the major hallmarks of PLAN including severe-early onset neurodegeneration, a motor deficit that correlates directly to TH levels, spheroid formation and iron accumulation within the basal ganglia. Thus, this mouse line is a useful tool for further research efforts to improve understanding of how these disease mechanisms give rise to the disease presentations seen in PLAN patients as well as to test novel therapies.

磷脂酶 A2G6 相关神经变性 (PLAN) 是一种罕见的早发性单基因神经退行性运动障碍，其目标是基底节和中枢和周围神经系统的其他区域；在患者中表现为一系列异质亚型。我们在这里描述了一个 B6.C3-Pla2g6 ^m1J/CxRwbPLAN 小鼠模型，在 90 天时出现早发性神经变性，这类似于在 PLAN 患者中观察到的疾病进展。纯合子小鼠的运动缺陷逐渐恶化，从 65 天开始表现为震颤，并在 90 天时发展为严重的运动功能障碍和增加跌倒。这种运动缺陷与黑质 (SN) 多巴胺能神经元中酪氨酸羟化酶 (TH) 蛋白表达的减少呈正相关，而没有任何神经元损失。Thy1-YFP 的荧光成像揭示了 SN 中的球体形成。纯合小鼠中的球状体强烈反映了在患者中观察到的球状体，并且证明与通过线悬试验测量的运动缺陷密切相关。球体的出现先于 TH 损失，球体数量增加与 TH 表达呈负相关。Perls/DAB 染色显示小鼠 SN 内存在铁积累。该小鼠模型捕捉了 PLAN 的许多主要特征，包括严重的早发性神经变性、与 TH 水平直接相关的运动缺陷、球体形成和基底神经节内的铁积累。因此，该小鼠品系是进一步研究工作的有用工具，以提高对这些疾病机制如何引起 PLAN 患者中所见疾病表现以及测试新疗法的理解。该小鼠模型捕捉了 PLAN 的许多主要特征，包括严重的早发性神经变性、与 TH 水平直接相关的运动缺陷、球体形成和基底神经节内的铁积累。因此，该小鼠品系是进一步研究工作的有用工具，以提高对这些疾病机制如何导致 PLAN 患者中出现的疾病表现以及测试新疗法的理解。该小鼠模型捕捉了 PLAN 的许多主要特征，包括严重的早发性神经变性、与 TH 水平直接相关的运动缺陷、球体形成和基底神经节内的铁积累。因此，该小鼠品系是进一步研究工作的有用工具，以提高对这些疾病机制如何引起 PLAN 患者中所见疾病表现以及测试新疗法的理解。