Abstract
Infantile neuroaxonal dystrophy (INAD) is a progressive, autosomal recessive neurodegenerative disease characterized by axonal dystrophy, abnormal iron deposition and cerebellar atrophy. This disease was recently mapped to PLA2G6, which encodes group VI Ca2+-independent phospholipase A2 (iPLA2 or iPLA2β). Here we show that genetic ablation of PLA2G6 in mice (iPLA2β-/-) leads to the development of cerebellar atrophy by the age of 13 months. Atrophied cerebella exhibited significant loss of Purkinje cells, as well as reactive astrogliosis, the activation of microglial cells, and the pronounced up-regulation of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, glial cell activation and the elevation in TNF-α and IL-1β expression occurred before apparent cerebellar atrophy. Our findings indicate that the absence of PLA2G6 causes neuroinflammation and Purkinje cell loss and ultimately leads to cerebellar atrophy. Our study suggests that iPLA2β-/- mice are a valuable model for cerebellar atrophy in INAD and that early anti-inflammatory therapy may help slow the progression of cerebellar atrophy in this deadly neurodegenerative disease.
Highlights
The phospholipase A2 (PLA2) family is a diverse group of enzymes that catalyzes the hydrolysis of the sn-2 fatty acyl bond of phospholipids to liberate free fatty acids and lysophospholipids [1]
The cerebella of the iPLA2b-/- mice were noticeably smaller than that of the age-matched wild type (WT) littermates (Fig. 1B) and they weighed nearly 25 percent less (Fig 1C). These findings indicated that iPLA2b-/- mice develop cerebellar atrophy by the age of 13 months that resembles the atrophy seen in humans with infantile neuroaxonal dystrophy (INAD)
To determine whether microglial activation occurs in the cerebella in the iPLA2b-/- mice, we examined the expression of ionized calcium binding adaptor molecule 1 (Iba-1) – a 17-kDa EF hand protein that is expressed in brain microglia and is up-regulated during their activation [22]
Summary
The phospholipase A2 (PLA2) family is a diverse group of enzymes that catalyzes the hydrolysis of the sn-2 fatty acyl bond of phospholipids to liberate free fatty acids and lysophospholipids [1]. Group VIA PLA2 (iPLA2b) has unique structural features, including eight N-terminal ankyrin repeats, caspase-3 cleavage sites, an ATP-binding domain, a serine lipase consensus sequence (GXSXG), a bipartite nuclear localization sequence, and a C-terminal calmodulin-binding domain [1]. Morgan et al [3] reported that mutations in PLA2G6 underlie human neurodegenerative disorders, infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA). INAD is a neurodegenerative disease with infantile onset and death as a teenager or in early adulthood. It is characterized by pathologic axonal swelling and spheroid bodies in the peripheral and central nervous systems (CNS) [4,5,6]. Mutations in PLA2G6 have recently been identified in many INAD patients, suggesting that iPLA2b plays an essential role in the CNS and the development of the disorder
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