Sumi-Akamaru Hisae, Beck Goichi, Kato Shinsuke, Mochizuki Hideki
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Japan.
Division of Neuropathology, Department of Brain and Neurosciences, Tottori University Faculty of Medicine, Yonago, Japan.
Neuropathology. 2015 Jun;35(3):289-302. doi: 10.1111/neup.12202. Epub 2015 May 6.
The PLA2G6 gene encodes group VIA calcium-independent phospholipase A2 (iPLA2 β), which belongs to the PLA2 superfamily that hydrolyses the sn-2 ester bond in phospholipids. In the nervous system, iPLA2 β is essential for remodeling membrane phospholipids in axons and synapses. Mutated PLA2G6 causes PLA2G6-associated neurodegeneration (PLAN) including infantile neuroaxonal dystrophy (INAD) and adult-onset dystonia-parkinsonism (PARK14), which have unique clinical phenotypes. In the PLA2G6 knockout (KO) mouse, which is an excellent PLAN model, specific membrane degeneration takes place in neurons and their axons, and this is followed by axonal spheroid formation. These pathological findings are similar to those in PLAN. This review details the evidence that membrane degeneration of mitochondria and axon terminals is a precursor to spheroid formation in this disease model. From a young age before the onset, many mitochondria with damaged inner membranes appear in PLA2G6 KO mouse neurons. These injured mitochondria move anterogradely within the axons, increasing in the distal axons. As membrane degeneration progresses, the collapse of the double membrane of mitochondria accompanies axonal injury near impaired mitochondria. At the axon terminals, the membranes of the presynapses expand irregularly from a young age. Over time, the presynaptic membrane ruptures, causing axon terminal degeneration. Although these processes occur in different degenerating membranes, both contain tubulovesicular structures, which are a specific ultrastructural marker of INAD. This indicates that two unique types of membrane degeneration underlie PLAN pathology. We have shown a new pathological mechanism whereby axons degenerate due to defective maintenance and rupture of both the inner mitochondrial and presynaptic membranes. This degeneration mechanism could possibly clarify the pathologies of PLAN, Parkinson disease and neurodegeneration with iron accumulation (NBIA), which are assumed to be due to the primary degeneration of axons.
PLA2G6基因编码VI A组钙非依赖性磷脂酶A2（iPLA2β），其属于磷脂酶A2超家族，可水解磷脂中的sn-2酯键。在神经系统中，iPLA2β对于轴突和突触中的膜磷脂重塑至关重要。突变的PLA2G6会导致PLA2G6相关神经退行性变（PLAN），包括婴儿神经轴索营养不良（INAD）和成人起病的肌张力障碍-帕金森综合征（PARK14），它们具有独特的临床表型。在PLA2G6基因敲除（KO）小鼠中，这是一种出色的PLAN模型，神经元及其轴突会发生特异性膜变性，随后形成轴突球状体。这些病理发现与PLAN中的相似。本综述详细阐述了线粒体和轴突终末的膜变性是该疾病模型中球状体形成的先兆这一证据。在发病前的幼年时期，PLA2G6 KO小鼠神经元中就出现了许多内膜受损的线粒体。这些受损的线粒体在轴突内顺向移动，在轴突远端增多。随着膜变性的进展，线粒体双层膜的塌陷伴随着线粒体受损附近的轴突损伤。在轴突终末，突触前膜从幼年起就不规则扩张。随着时间的推移，突触前膜破裂，导致轴突终末变性。尽管这些过程发生在不同的变性膜中，但两者都含有微管泡状结构，这是INAD的一种特异性超微结构标志物。这表明两种独特类型的膜变性是PLAN病理学的基础。我们展示了一种新的病理机制，即由于线粒体内膜和突触前膜的维持缺陷和破裂，轴突发生变性。这种变性机制可能有助于阐明PLAN、帕金森病和铁蓄积性神经退行性变（NBIA）的病理学，这些疾病被认为是由于轴突的原发性变性所致。
