A novel temporal‐predominant neuro‐astroglial tauopathy associated with TMEM106B gene polymorphism in FTLD/ALS‐TDP,Brain Pathology

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A novel temporal‐predominant neuro‐astroglial tauopathy associated with TMEM106B gene polymorphism in FTLD/ALS‐TDP
Brain Pathology ( IF 5.8 ) Pub Date : 2020-12-12 , DOI: 10.1111/bpa.12924
Jorge J Llibre-Guerra _{1,

2,

3} , Suzee E Lee ₁ , Claudia K Suemoto _{4,

5} , Alexander J Ehrenberg _{1,

6} , Gabor G Kovacs _{7,

8,

9} , Anna Karydas ₁ , Adam Staffaroni ₁ , Elisa De Paula Franca Resende _{1,

3,

10} , Eun-Joo Kim ₁₁ , Ji-Hye Hwang ₁ , Eliana Marisa Ramos ₁₂ , Kevin J Wojta ₁₂ , Lorenzo Pasquini ₁ , Shirley Yin-Yu Pang ₁₃ , Salvatore Spina ₁ , Isabel E Allen _{3,

14} , Joel Kramer ₁ , Bruce L Miller ₁ , William W Seeley _{1,

15} , Lea T Grinberg _{1,

3,

4,

15}

Affiliation

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
National Institute of Neurology and Neurosurgery, La Habana, Cuba.
Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, USA.
Biobank for Aging Studies, LIM-22, Department of Pathology, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Division of Geriatrics, Department of Clinical Medicine, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, USA.
Institute of Neurology, Medical University Vienna, Vienna, Austria.
Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada.
Laboratory Medicine Program & Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
Grupo de Pesquisa em Neurologia Cognitiva e do Comportamento, Departamento de Clínica Médica, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Busan, Republic of Korea.
Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Division of Neurology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China.
Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
Department of Pathology and Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.

Polymorphisms in TMEM106B, a gene on chromosome 7p21.3 involved in lysosomal trafficking, correlates to worse neuropathological, and clinical outcomes in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) with TDP‐43 inclusions. In a small cohort of C9orf72 expansion carriers, we previously found an atypical, neuroglial tauopathy in cases harboring a TMEM106B rs1990622 A/A genotype. To test whether TMEM106B genotype affects the risk of developing atypical tauopathy under a recessive genotype model (presence versus absence of two major alleles: A/A vs. A/G and G/G). We characterized the atypical tauopathy neuropathologically and determined its frequency by TMEM106B rs1990622 genotypes in 90 postmortem cases with a primary diagnosis of FTLD/ALS‐TDP [mean age at death 65.5 years (±8.1), 40% female]. We investigated the effect of this new atypical tauopathy on demographics and clinical and neuropsychological metrics. We also genotyped TMEM106B in an independent series with phenotypically similar cases. Sixteen cases (16/90, 17.7 %) showed the temporal‐predominant neuro‐astroglial tauopathy, and 93.7% of them carried an A/A genotype (vs. ~35% in a population cohort). The odds ratio of FTLD/ALS‐TDP individuals with the A/A genotype showing neuro‐astroglial tauopathy was 13.9. Individuals with this tauopathy were older at onset (p = 0.01). The validation cohort had a similarly high proportion of rs1990622 A/A genotype. TDP‐43 and tau changes co‐occur in a subset of neurons. Our data add to the growing body of evidence that TMEM106B polymorphisms may modulate neurodegeneration. A distinctive medial temporal predominant, 4‐repeat, neuro‐astroglial tauopathy strongly correlates to TMEM106B A/A genotype in FTLD/ALS‐TDP cases.

中文翻译：

一种与 FTLD/ALS-TDP 中 TMEM106B 基因多态性相关的新型时间主导型神经星形胶质细胞 tau 病变

TMEM106B中的多态性是染色体 7p21.3 上参与溶酶体运输的基因，与额颞叶变性 (FTLD) 和具有 TDP-43 包涵体的肌萎缩侧索硬化 (ALS) 中较差的神经病理学和临床结果相关。在一小群C9orf72扩增携带者中，我们之前在携带TMEM106B rs1990622 A/A 基因型的病例中发现了一种非典型的神经胶质 tau 病变。测试TMEM106B基因型是否影响在隐性基因型模型下发生非典型 tau 病的风险（存在与不存在两个主要等位基因：A/A 与 A/G 和 G/G）。我们在神经病理学上表征了非典型 tau 病并通过TMEM106B确定了它的频率90 例初步诊断为 FTLD/ALS-TDP 的 rs1990622 基因型[平均死亡年龄 65.5 岁 (±8.1)，40% 为女性]。我们研究了这种新的非典型 tau 蛋白病对人口统计学、临床和神经心理学指标的影响。我们还在具有表型相似病例的独立系列中对TMEM106B进行了基因分型。16 例 (16/90, 17.7 %) 表现出颞叶为主的神经星形胶质细胞 tau 病变，其中 93.7% 携带 A/A 基因型（与人群队列中的约 35% 相比）。具有显示神经星形胶质细胞 tau 病的 A/A 基因型的 FTLD/ALS-TDP 个体的比值比为 13.9。患有这种 tau 病的个体发病时年龄较大（p = 0.01）。验证队列具有类似高比例的 rs1990622 A/A 基因型。TDP-43 和 tau 变化在神经元子集中同时发生。我们的数据增加了越来越多的证据表明TMEM106B多态性可能调节神经变性。在 FTLD/ALS-TDP 病例中，一种独特的内侧颞叶主导的、4 次重复的神经星形胶质细胞 tau 病与TMEM106B A/A 基因型密切相关。

更新日期：2020-12-12

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