Extensive aggregation of α-synuclein and tau in juvenile-onset neuroaxonal dystrophy: an autopsied individual with a novel mutation in the PLA2G6 gene-splicing site
© Riku et al.; licensee BioMed Central Ltd. 2013
Received: 09 February 2013
Accepted: 05 April 2013
Published: 09 May 2013
Infantile neuroaxonal dystrophy (INAD) is a rare autosomal-recessive neurodegenerative disorder. Patients with INAD usually show neurological symptoms with infant onset and die in childhood. Recently, it was reported that mutations in the PLA2G6 gene cause INAD, but neuropathological analysis of genetically confirmed individuals with neuroaxonal dystrophy has been limited.
Here, we report a Japanese individual with neuroaxonal dystrophy associated with compound heterozygous mutations in the PLA2G6 gene. A novel splice-site mutation resulting in skipping and missense mutations (p.R538C) in exon 9 was identified in the patient. This patient initially presented with cerebellar ataxia at the age of 3 years, which was followed by symptoms of mental retardation, extrapyramidal signs, and epileptic seizure. The patient survived until 20 years of age. Neuropathological findings were characterized by numerous axonal spheroids, brain iron deposition, cerebellar neuronal loss, phosphorylated alpha-synuclein-positive Lewy bodies (LBs), and phosphorylated-tau-positive neurofibrillary tangles. In particular, LB pathology exhibited a unique distribution with extremely severe cortical involvement.
Our results support a genetic clinical view that compound heterozygous mutations with potential residual protein function are associated with a relatively mild phenotype. Moreover, the severe LB pathology suggests that dysfunction of the PLA2G6 gene primarily contributes to LB formation.
Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive neurodegenerative disorders that are pathologically characterized by the presence of axonal spheroids and iron deposition in the brain [1–3]. These neurodegenerative diseases consist of a clinically and genetically heterogeneous group of disorders, including pantothenate kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz disease), infantile neuroaxonal dystrophy (INAD), and an unknown gene mutation-linked idiopathic neuroaxonal dystrophy [1, 2, 4]. PKAN is caused by mutations in the pantothenate kinase 2 (PANK2) gene, which accounts for the majority of NBIA patients . Recently, it was reported that mutations in the phospholipase A2 group VI (PLA2G6) gene cause INAD , which is a rare autosomal-recessive neurodegenerative disorder. Patients with INAD usually present with psychomotor regression, truncal hypotonia, progressive ataxia, extrapyramidal symptoms, fast waves on an electroencephalogram, and neuro-ophthalmological abnormalities (e.g., optic atrophy, nystagmus, and strabismus) with infant onset and die in childhood [1, 4, 6]. However, in rare cases, patients with NAD caused by PLA2G6 mutations present with heterogeneous neurological manifestations with onset past infanthood and survive until adulthood with a slower disease progression [1, 7, 8]. In addition, mutations of the PLA2G6 gene cause early onset dystonia-parkinsonism (PARK-14), which is clinically distinguished from NAD by good L-dopa responsiveness, L-dopa–induced dyskinesia, and dementia. These characteristics have been typically observed in patients with an older age of onset and with a longer disease duration compared to NAD, with no evidence of cerebellar symptoms . Thus, these clinical phenotypes are collectively termed as PLA2G6-associated neurodegeneration .
We report a Japanese individual with neuroaxonal dystrophy that was associated with a novel compound heterozygous mutation in a splicing site of the PLA2G6 gene. The clinical phenotype of this patient was atypical for INAD, occurred during late disease onset, and prolonged the disease course. Histopathological data revealed the presence of neuroaxonal spheroids, brain iron depositions, and cerebellar degeneration. Moreover, numerous Lewy bodies (LBs) and neurofibrillary tangles (NFTs), which are pathological hallmarks of Parkinson’s disease (PD) and Alzheimer’s disease (AD), respectively, were observed. Until recently, neuropathological analysis of genetically confirmed neuroaxonal dystrophy has been strongly limited due to a small number of patients [1, 8]. In this study, we describe the clinicopathological characteristics of the patient and discuss the neuropathological implication of LBs and NFTs compared with PD and AD.
Materials and methods
The postmortem interval was 5 hours. The brain and spinal cord were fixed in 20% neutral formalin. Samples obtained from the main representative regions of the brain and spinal cord were embedded in paraffin, sectioned into 4.5-μm-thick slides, and stained with hematoxylin and eosin (H&E), Klüver-Barrera staining, Prussian blue methods, and Gallyas-Braak (GB) staining. Immunohistochemical studies were performed on 4.5-μm-thick sections using an ENVISION kit (Dako) with diaminobenzidine (DAB; Wako, Osaka, Japan) as a chromogen. The primary antibodies used were anti-phosphorylated alpha-synuclein (p-α-synuclein) (pSyn#64, monoclonal mouse, 1:1000; Wako Pure Chemical Industries, Osaka, Japan), anti-ubiquitin (polyclonal rabbit, 1:2000; Dako), anti-amyloid-beta peptide (6F/3D, monoclonal mouse, 1:200; Dako), phosphorylated tau (p-tau) (AT8, monoclonal mouse, 1:2000; Innogenetics, Zwijndrecht, Belgium), anti- TDP-43 (TARDBP, polyclonal rabbit, 1:2500; ProteinTech, IL, USA), and anti-phosphorylated neurofilament (p-NF) (2F11, monoclonal mouse, 1:600; Dako). For double-immunofluorescence labeling, brain tissues obtained from the amygdala, oculomotor nucleus, and substantia nigra were sectioned into 4.5-μm-thick slides. The primary antibodies were anti-p-α-synuclein antibody and AT8 antibody. The secondary antibodies were goat anti-mouse IgG coupled with either Alexa Fluor 568 (1:300, emission peak 603 nm, Molecular Probes, OR, USA) or Alexa Fluor 488 (1:300, emission peak 517 nm, Molecular Probes). The slides were examined via confocal microscopy at × 200 and × 400 magnification using a Zeiss LSM 710 laser scanning confocal microscope.
For electron microscopy, sections from the cingulate gyrus were fixed in 4% glutaraldehyde. The sections were washed in phosphate buffer, postfixed with osmium tetroxide, dehydrated in a graded series of ethanol, and embedded in Epon. Ultrathin sections were stained with uranyl acetate and lead citrate.
Western blotting analysis of α-synuclein
Proteins expressed in the amygdala and parahippocampal gyrus of the autopsied patient and three control subjects were extracted as previously described [10, 11]. Briefly, we fractionated the samples by resolubilization in increasingly stringent buffers (Tris-buffered saline, 1% Triton X-100, 1% sarcosyl, 8 M urea) as previously described. Equal amounts of supernatant protein were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. The mouse monoclonal antibody LB509 (Zymed Laboratories, South San Francisco, California) was used to detect α-synuclein. The monoclonal antibody pSyn#64 (Wako, Japan) specifically recognizes phosphorylated α-synuclein at serine 129 .
Genomic DNA was extracted from the frozen liver tissue of the patient using a standard procedure. Mutational analysis was performed using sequences of both strands of all of the PCR-amplified coding exons and the flanking intronic sequences of PLA2G6, PANK-2, SNCA, parkin, PINK-1, and DJ-1. Expansion of the CAG repeats of the SCA1, SCA3, DRPLA, and Huntington’s disease genes was also examined. Genetic analysis of PLA2G6 was also performed in the patient’s parents. Total RNA was isolated from frozen brain tissue of the patient, and cDNA was synthesized using a High-Capacity cDNA Reverse Transcription kit (Applied Biosystems). RT-PCR was performed using primer pairs to amplify the coding regions of the PLA2G6 gene spanning exons 8–13 (5′-caacgtggagatgatcaagg-3′ and 5-gtcagcatcaccttgggttt-3′) and exons 9–13 (5′-ggaaggcgatcttgactctg-3′ and 5′-gtcagcatcaccttgggttt-3′). The institutional review board approved this study.
Histopathologically, severe neuronal loss and gliosis were observed in the cerebral cortex, brainstem gray matter, and cerebellar cortex. In the cerebrum, neuronal loss was marked in the cingulate gyrus, fronto-temporal cortex, insular cortex, amygdala, and hippocampus. In the brain stem, neurons in the SN were markedly depleted, and the remaining neurons had low melanin content. The locus ceruleus (LC) showed moderate neuronal loss, but the neurons in the dorsal motor nucleus of the vagus were relatively spared. The cerebellar cortex showed severe neuronal loss (Figure 2c,d), particularly in the granule cell (gc) layer, and the parallel fibers in the molecular layer were strongly reduced (Figure 2c,d,h). Purkinje cells (Pcs) were severely depleted and often ectopically scattered at random in the molecular layer (Figure 2d). The spinal cord exhibited myelin pallor of the gracile fasciculus with gliosis.
In addition, we observed axonal spheroids throughout the central nervous system (CNS), particularly in the cerebral cortex, putamen (Figure 2e-g), caudate nucleus, nucleus accumbens, hypothalamus, SN, gracile nucleus, and spinal cord. The cerebellum contained numerous dystrophic axons called ‘torpedoes’ in the Pc and gc layers (Figure 2h). The diameters of the spheroids ranged from 10 to 20 μm, but the spinal cord contained larger-sized spheroids of 40–70 μm in diameter. Various spheroids were immunoreactive against anti-p-NF (Figure 2g,h) and anti-ubiquitin antibodies. We found no spheroids in the sympathetic ganglia, dorsal root ganglia, spinal roots, peripheral nerve fibers in the skin, or the enteric plexus. Brown-pigmented, Prussian blue-positive iron granules were scattered around the vessels and throughout the neuropil in the putamen, internal segment of the GP, caudate nucleus, thalamus, pars compacta of the SN, and periaqueductal gray matter (Figures 2i,j, 4c).
Using double-immunofluorescence labeling in the amygdala, p-tau-positive NFTs and p-α-synuclein-positive cortical LBs often co-labeled in the same neuron (Figure 3m-o). In contrast, neurons in the midbrain did not show co-labeling of LBs and NFTs (data not shown).
On electron microscopy, LBs from the cingulate gyrus consisted of closely packed 6- to 10-nm-thick granular and filamentous structures. The filaments were arranged at random without a clear central zone density. These findings were similar those observed in cortical-type LBs in the DLB  (Figure 3g,h).
Western blotting analysis of α-synuclein
We next investigated whether the splice-site mutation caused an alteration in the splicing of PLA2G6 using RT-PCR analysis of total RNA extracted from the patient’s frozen tissue. To examine the mRNA expression of PLA2G6 in the patient’s brain, two primer pairs were designed to amplify cDNA fragments encompassing exons 8 to 13 (primers A-C) and 9 to 13 (primers B-C), respectively (Figure 6c). In the control samples, two alternative splicing variants were amplified using the primer pairs A-C. Sequence analysis of the fragments in the control samples revealed that these variants corresponded to two previously reported isoforms of PLA2G6 mRNA, with and without the 162-bp exon 9, respectively . In the patient, the 700-bp fragment containing exon 9 was nearly undetectable by RT-PCR using the primer pair A-C. RT-PCR amplification using the primer pair B-C revealed that the 600-bp cDNA fragment containing exon 9 found in the control samples was less expressed in the patient (Figure 6d).
INAD is a rare, autosomal-recessive neurodegenerative disorder with infant onset, and patients usually die in childhood [1, 4, 6]. In an INAD cohort with PLA2G6 mutations previously described by Gregory et al., symptoms began between 5 months and 2.5 years of age . Wu et al. reported that half of INAD patients with a disease course of 2–5 years became vegetative . In this study, the patient’s initial neurological manifestation was cerebellar ataxia at the age of 3 years, which was later accompanied by mental retardation, dystonia, and seizures. The patient survived until the age of 20 years. His clinical phenotype was atypical for INAD; the disease onset and progression were delayed and slower, and there was no indication of truncal hypotonia, neuro-ophthalmologic abnormalities, or fast rhythms on an electroencephalogram throughout the clinical course. Gregory et al. previously described six patients in their patient registry with PLA2G6 mutation who exhibited variable clinical phenotypes with late onset (average 4.4 years, range 1.5-6.5 years) [1, 2]. This phenotype was referred to as atypical neuroaxonal dystrophy (ANAD). The clinical phenotype of our patient might be classified as ANAD. Moreover, patients with a slower disease progression and heterogeneous clinical pictures have been occasionally described in other series of INAD patients [7, 8]. Currently, it is speculated that patients with mutant forms of the PLA2G6 gene display a complete absence of protein, which is associated with a severe INAD profile, whereas patients with compound heterozygous mutations potentially exhibit residual protein function and have a less severe phenotype . Our genetic findings further support this genotype-phenotype correlation.
Summary of the neuropathological findings in autopsied patients with PLA2G6 gene mutations in the literature
Age at onset
Age at death
Spheroids in the CNS
Spheroids in the PNS
Neuronal loss in the cerebellum
Accumulation of alpha synuclein
Accumulation of tau
gc and Pc
gc and Pc
gc and Pc
gc and Pc
gc and Pc
LB pathology has been identified in all six patients reviewed [1, 8]. A recent study reported that LB pathology was not observed in patients with the PANK2 gene mutation . Moreover, earlier case reports describing neuroaxonal dystrophy or brain iron accumulation with abundant LBs may have been describing patients with PLA2G6 gene mutations [20–22]. We demonstrated that the morphological, ultrastructural, and biochemical properties of LBs in this patient were identical to those in PD and diffuse Lewy body disease (DLB) patients [12, 16, 23]. Furthermore, the spatial distribution of LB pathology showed cortical involvement that exceeded that of the end stage of sporadic PD or the diffuse neocortical type of DLB [13, 14]. Previous autopsy reports of INAD and ANAD have also described marked cortical involvement of LBs [1, 8]. In contrast, the dorsal nucleus of the vagus nerve and olfactory bulbs were mildly affected in our patient, and the cardiac nerve fibers and enteral nerve plexus contained no p-α-synuclein aggregation, although these regions have been described as constant and early affected regions in sporadic PD and DLB [24, 25]. The distribution of LB pathology in INAD and ANAD may tend to be more severe in the cerebral cortices compared to the medulla oblongata or peripheral autonomic neurons, which differs from the typical topography observed in sporadic PD and DLB. NFT pathology was another neuropathologial characteristic of interest in patients with INAD and ANAD. In our patient, NFTs and p-tau-positive threads predominantly appeared in the limbic system, which was similar to AD in Braak’s stage IV . However, neither this nor previously reported patients with PLA2G6 gene mutations exhibited senile plaques, which contrasts with the typical neuropathology observed in AD . Importantly, NFT pathology has been frequently observed in patients with sporadic PD or DLB [26, 27], and LBs and NFTs often coexist in the same neurons, particularly those located in the limbic areas . Our double-immunofluorescence results are consistent with findings in sporadic PD and DLB. Thus, further investigation in multiple patients on the association between NFTs and LB pathology and the implications of NFT pathology in INAD and ANAD are required.
The PLA2G6 gene encodes iPLA2-Via, which is a critical protein in lipid membrane homeostasis . Recent reports using Pla2g6-knockout mice demonstrated the presence of axonal spheroids in which tubulovesicular membranes accumulated [29–32]. In contrast, the pathological mechanism that contributes to LB formation in INAD and ANAD remains to be elucidated. LBs are secondarily present in several situations other than sporadic PD/DLB (e.g., sporadic or familial AD or Niemann-Pick disease type C) or may be incidentally found in healthy elderly individuals [33–36]. However, our neuropathological results and previous studies have demonstrated that LB pathology in patients with PLA2G6 gene mutations shows a high prevalence and displays an extremely severe phenotype, particularly in the cerebral cortices. These findings suggest that defects in PLA2G6 primarily contribute to the formation of LBs.
Our results demonstrate the clinical heterogeneity of neuroaxonal dystrophy with PLA2G6 gene mutations and support a genetic clinical view that compound heterozygous mutations that potentially result in residual protein function are associated with a less severe phenotype. Neuropathologically, CNS involvement with LBs was striking and exhibited a unique topography compared with PD. Thus, further investigations on the process of LB formation caused by loss of PLA2G6 gene function may provide new insights into the pathological mechanism of neuroaxonal dystrophy and LB formation.
Written informed consent was obtained from the patient’s parents for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in chief of this journal.
This work was supported by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan. The study was approved by the ethics committee of Juntendo University and Niigata University, and all subjects gave informed consent.
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