TAR DNA结合蛋白43在肌萎缩侧索硬化症中致病机制的研究进展

肌萎缩侧索硬化症(ALS)是一种主要累及上、下运动神经元的神经系统退行性疾病。TAR DNA结合蛋白43(TDP-43)蛋白是大部分ALS患者中特征性的病理性聚集蛋白。TDP-43蛋白致ALS的机制尚不明确,可归纳为以下两种假说:"功能缺失"和"功能获得"。相关机制有:①TDP-43蛋白稳态与自噬密切相关;②TDP-43蛋白与RNA结合,干扰RNA代谢,并与应激颗粒的形成密切相关;③TDP-43蛋白聚集与线粒体功能障碍相互影响;④TDP-43蛋白异常聚集影响细胞骨架结构,致轴突运输异常,并引起神经肌肉肉接头功能障碍;⑤外泌体能降解胞浆TDP-43蛋白聚集并促进其在细胞之间的扩散等。本文就TDP-43蛋白致ALS的机制的最新进展做一综述。     

利美尼定促进肌萎缩侧索硬化相关蛋白质TDP-43降解的研究

目的 探索利美尼定(RIL)对肌萎缩侧索硬化(ALS)相关蛋白质TAR DNA结合蛋白43(TDP-43)降解的影响.方法 用瞬时转染的方法在运动神经元样细胞系NSC-34中过表达WT TDP-43,与家族型ALS相关的Q331K TDP-43、M337V TDP-43突变蛋白、TDP-43的两种C末端片段TDP-25...     

从运动神经元的TDP-43蛋白表达和ADAR2活性探讨肌萎缩侧索硬化症的发病机制

肌萎缩性侧索硬化症(ALS)是以上下两级运动神经元进行性丢失为特征的神经系统变性疾病,是运动神经元病(MND)中最常见的类型。运动神经元中的病理性TDP-43是ALS的病理特征。此外,散发性ALS运动神经元中作用于RNA的次黄嘌呤腺苷脱氢酶(ADAR2)减少、具有未经编辑Q/R位点的谷氨酸受体2(GluR2)表达增加,α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体(AMPAR)属性受影响,Ca2+通透性增加,Ca2+流入胞质增加导致神经元死亡。ALS运动神经元死亡包含病理性TDP-43和ADAR2活性下降,两种病理变化可能在细胞死亡中存在一定联系。ADAR2 mRNA是TDP-43蛋白的靶RNA,TDP-43蛋白在ADAR2的表达中起调节作用。近年来,研究者探讨ALS的基因治疗可能性:动物实验结果提示,外周静脉给予9型腺相关病毒载体(AAV9),可上调鼠运动神经元ADAR2,引发外源性ADAR2在中枢神经元表达,从而有效防治运动功能障碍。运动神经元的获救可能与TDP-43基因的正常表达有关。AAV9介导的ADAR2基因植入可能为ALS的基因治疗提供新的前景。     

TAR DNA结合蛋白43在肌萎缩侧索硬化症中致病机制的研究进展

肌萎缩侧索硬化症（ALS）是一种主要累及上、下运动神经元的神经系统退行性疾病。TAR DNA结合蛋白43（TDP-43）蛋白是大部分ALS患者中特征性的病理性聚集蛋白。TDP-43蛋白致ALS的机制尚不明确,可归纳为以下两种假说："功能缺失"和"功能获得"。相关机制有：①TDP-43蛋白稳态与自噬密切相关;②TDP-43蛋白与RNA结合,干扰RNA代谢,并与应激颗粒的形成密切相关;③TDP-43蛋白聚集与线粒体功能障碍相互影响;④TDP-43蛋白异常聚集影响细胞骨架结构,致轴突运输异常,并引起神经肌肉肉接头功能障碍;⑤外泌体能降解胞浆TDP-43蛋白聚集并促进其在细胞之间的扩散等。本文就TDP-43蛋白致ALS的机制的最新进展做一综述。     

肌萎缩侧索硬化患者血浆和脑脊液谷氨酸改变及利鲁唑对血浆谷氨酸的影响

目的 :了解肌萎缩侧索硬化 (ALS)患者血浆和脑脊液谷氨酸浓度改变 ,以及药物干预对谷氨酸水平的影响。方法 :应用HPLC方法对ALS患者进行血浆和脑脊液谷氨酸测定。结果 :①患者血浆中存在兴奋性谷氨酸显著增高 ,谷氨酸浓度与性别、年龄、病程均无关。②力鲁唑 (力如太 )治疗 1个月后 ,血浆谷氨酸浓度下降 ,而环磷酰胺治疗变化不明显。③脑脊液中谷氨酸浓度未见明显变化。结论 :ALS患者存在谷氨酸代谢异常 ,但谷氨酸可能不是ALS致病的惟一途径。     

散发性肌萎缩侧索硬化发病机制探讨:谷氨酸受体2Q/R部位RNA无效编辑和病理性TDP-43

谷氨酸受体2(glutamate receptor A2,Glu A2)Q/R部位编辑率降低以及相关的RNA2的次黄嘌呤腺苷脱氨酶(adenosine deaminase acting on RNA2,ADAR2)的异常与病理性反式激活应答DNA结合蛋白43(transactivation response DNA-binding protein 43-k D,TDP-43)可同时发生在肌萎缩侧索硬化(amyotrophic lateral sclerosis,ALS)患者的运动神经元中,提示在ALS患者中,这些异常分子病变之间可能存在关联。条件性敲除ADAR2基因的ALS小鼠可表现为运动神经元的缓慢死亡。因为缺乏ADAR2可引起TDP-43的异常分布和聚集,引发神经细胞毒性,继而加速运动神经元变性及死亡。本文总结了Glu A2 Q/R部位RNA无效编辑的规律和病理性TDP-43在ALS发病中的作用,并讨论了可能影响ADAR2介导的RNA无效编辑的相关因素,以期为研发新的ALS治疗方法提供参考依据。     

肌萎缩侧索硬化症相关TDP-43降解机制的研究

目的探索肌萎缩侧索硬化症(ALS)相关TDP-43的降解机制。方法用瞬时转染的方法在运动神经元样细胞系NSC-34中过表达野生型(role of wild-type,WT)WT TDP-43,与家族型ALS相关的Q331K TDP-43、M337V TDP-43突变蛋白、TDP-43的两种C末端片段TDP-25和TDP-35,再给予自噬、蛋白酶体通路的特异性诱导剂和阻断剂,通过蛋白印迹方法检测5种TDP-43以及自噬标记物LC3-Ⅱ的表达水平。结果在自噬诱导剂作用下,各组LC3-Ⅱ的表达升高,同时两种突变TDP-43及其C末端片段的表达明显减少,在自噬通路和蛋白酶体阻断剂作用下突变TDP-43及其C末端片段表达水平明显增多,而WT TDP-43的蛋白表达水平仅在蛋白酶体阻断剂作用时增多。结论 WT TDP-43主要经由蛋白酶体途径降解,Q331K TDP-43、M337V TDP-43及其C末端片段经由蛋白酶体途径和自噬两种途径降解。     

核质转运障碍在肌萎缩侧索硬化-额颞痴呆发病机制中的研究进展

肌萎缩侧索硬化(amyotrophic lateral sclerosis,ALS)和额颞痴呆(frontotemporal dementia,FTD)是以选择性、进行性神经元死亡为主要特征的神经系统变性疾病,给社会和家庭带来沉重负担。越来越多的证据表明,ALS与FTD的临床表现、病理特征和遗传特征有所重叠。与单纯的ALS或FTD相比,ALS-FTD(ALS合并FTD)的疾病进展速度更快,患者的生存期也更短。目前,尚未阐明ALS和FTD的发病机制。许多研究揭示,ALS与FTD存在共同的病理基础:神经系统残存的神经元及胶质细胞内存在反式激活应答DNA结合蛋白43(transactivation response DNA-binding protein 43 k Da,TDP-43)阳性包涵体。研究发现,ALS和FTD患者中枢神经系统内的TDP-43蛋白失去正常的细胞核定位,而在细胞质内聚集形成包涵体。由此推测,TDP-43蛋白的核内转入机制缺陷导致其正常功能丢失及获得性神经毒性可能是ALS-FTD发病的始动因素之一。本文对核质转运障碍在ALS-FTD发病机制中的最新研究进展进行综述。     

肌萎缩侧索硬化患者血浆转化生长因子-α水平的变化及其意义

目的探讨肌萎缩侧索硬化(ALS)患者血浆转化生长因子-α(TGF-α)水平及其临床意义。方法采用MILLIPLEX MAP液相芯片技术检测ALS患者血浆TGF-α水平,针对该指标,进行统计学分析,系统研究ALS患者与正常对照的关系、患者亚组(性别亚组、年龄亚组、病程亚组、起病部位亚组、功能评分亚组)与正常对照之间的关系。结果与正常对照相比,ALS患者血浆TGF-α水平显著升高(P0.05),各个患者亚组血浆TGF-α水平均显著升高(均P0.05);病程12个月患者比病程≤12个月患者的血浆TGF-α水平显著升高(P0.05),而其它患者亚组之间,血浆TGF-α水平均无统计学差异(均P0.05);此外,该指标水平变化与病程统计正相关(RRho=0.314,P=0.030)。结论血浆TGF-α在ALS的炎症机制中可能起到促进病情进展的作用,该指标有可能会成为推断疾病进展的潜在生物学标记。本文的相关试探性研究有望为酪氨酸激酶抑制剂等治疗ALS的措施提供更多的理论依据。     

Do not curse the darkness of the spinal cord,light TDP-43

正Cytoplasmic inclusions containing the transactivation response element (TAR) DNAbinding protein-43 (TDP-43) ag gregates are hallmarks of neurodegenerative disorders,such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (Arai et al., 2006;     

Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis

There is mounting pathological, biochemical and genetic evidence that the metabolism and aggregation of the 43-kDa transactive response (TAR)-DNA-binding protein (TDP-43) play a crucial role in the pathogenesis of sporadic and some forms of familial amyotrophic lateral sclerosis (ALS). Recently, it was reported using an ELISA system that elevated levels of TDP-43 were detected in plasma samples from patients with Alzheimer’s disease and frontotemporal dementia, compared to healthy controls. To determine whether quantification of TDP-43 in cerebrospinal fluid (CSF) is potentially informative in the diagnosis of ALS, we measured the concentration, by a similar ELISA method, of TDP-43 in CSF from 30 patients with ALS (diagnosed according to the revised El Escorial criteria) and 29 age-matched control patients without any neurodegenerative disease. We found that, as a group, the ALS patients had significantly higher levels of TDP-43 in their CSF than the age-matched controls (6.92 ± 3.71 ng/ml in ALS versus 5.31 ± 0.94 ng/ml in controls, p < 0.05), with levels of TDP-43 in CSF elevated beyond 95% upper confidence level for the control group in six (20%) of the patients with sporadic ALS. All the six patients with higher levels of CSF TDP-43 were examined within 10 months of the onset of illness. The patients examined within 10 months of onset showed significantly higher levels of CSF TDP-43 (8.24 ± 4.72 ng/ml) than those examined after 11 months or more of onset (5.41 ± 0.66 ng/ml, p < 0.05). These results suggest that the levels of TDP-43 in CSF may increase in the early stage of ALS. We also confirmed the existence of the TDP-43 protein in CSF from some patients with ALS, and a control subject, by western blotting of proteins immunocaptured from the CSF samples. Raised TDP-43 levels in the CSF may preempt the formation of TDP-43 pathology in the central nervous system, or correlate with early-stage TDP-43 pathology, and accordingly be a biomarker for the early stage of ALS.     

Cytoplasmic accumulation of TDP-43 in circulating lymphomonocytes of ALS patients with and without TARDBP mutations

TDP-43, encoded by TARDBP, is a ubiquitously expressed, primarily nuclear protein. In recent years, TDP-43 has been identified as the major pathological protein in ALS due to its mislocalisation in the cytoplasm of motor neurons of patients with and without TARDBP mutations and expression in forms that do not match its predicted molecular weight. In this study, the TDP-43 profile was investigated using western immunoblot analysis in whole lysates, nuclei and cytoplasm of circulating lymphomonocytes from 16 ALS patients, 4 with (ALS/TDP+) and 12 without (ALS/TDP-) TARDBP mutations in the protein C-terminal domain, and thirteen age-matched, healthy donors (controls). Three disease-unaffected first-degree relatives of an ALS/TDP+ patient were also included: one carried the parent mutation (Rel/TDP+) whereas the other two did not (Rel/TDP-). In all ALS patients, relatives and controls, TDP-43 retained the predicted molecular weight in whole cell lysates and nuclei, but in the cytoplasm its molecular weight was slightly smaller than expected. In quantitative terms, TDP-43 was expressed at approximately the same levels in whole cell lysates of ALS patients, relatives and controls. In contrast, TDP-43 accumulated in the cytoplasm with concomitant nuclear depletion in all ALS/TDP+ patients, in about 50% of ALS/TDP- patients and in the Rel/TDP+ subject compared to the controls. In the remaining ALS/TDP- patients and in the two Rel/TDP- subjects, TDP-43 matched the control levels in both subcellular compartments. Were these findings further confirmed, circulating lymphomonocytes could be informative of TDP-43 mislocalisation in nervous tissue and used as a biomarker for future disease risk.     

Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis

TMEM106B has recently been identified as a genetic risk factor for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). Amyotrophic lateral sclerosis (ALS), like FTLD-TDP, is characterized by pathological TDP-43 inclusions. We therefore investigated whether FTLD-TDP-associated risk genotypes at TMEM106B (1) contribute to risk of developing ALS or (2) modify the clinical presentation in ALS. Detailed clinical and pathological information from 61 postmortem ALS patients was collected by database query, retrospective chart review, and histopathological slide review. DNA from these patients, as well as 24 additional ALS patients, was genotyped for three TMEM106B single nucleotide polymorphisms known to confer increased risk of FTLD-TDP. Associations between TMEM106B genotype and ALS were investigated by comparing TMEM106B genotypes in ALS patients (n?=?85) and normal controls (n?=?553), and associations between TMEM106B genotype and clinical and pathologic features were explored using linear regression. Multivariate linear models were used to evaluate the contributions of TMEM106B genotype and TDP-43 pathology to cognitive performance in ALS as measured by a phonemic verbal fluency test. We found that TMEM106B genotypes did not differ between ALS patients and normal controls. However, protective alleles at TMEM106B were significantly associated with preserved cognition in ALS patients, with the strongest association seen under a major-allele-dominant genetic model. While lower TDP-43 pathology scores and protective alleles at TMEM106B both correlated with better cognitive scores, these factors were not correlated with each other and demonstrated independent effects. These findings implicate the FTLD-TDP risk gene TMEM106B in the development of cognitive impairment in ALS.     

TDP-43-immunoreactive neuronal and glial inclusions in the neostriatum in amyotrophic lateral sclerosis with and without dementia

TDP-43 is a major component of ubiquitin-positive, tau-negative inclusions in amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration. We immunohistochemically examined the neostriatum from 14 cases of classic ALS (cALS), six cases of ALS with dementia (ALS-D), and 20 control subjects. TDP-43-positive, crescent or circular inclusions were found in neostriatal small neurons in 19 of 20 cases of ALS, but not in controls. Two types of inclusions were found in the large neurons: ubiquitin-positive, TDP-43-negative rod-like inclusions, and ubiquitin- and TDP-43-positive pleomorphic inclusions. The latter were specific to ALS; they were found in seven cases of cALS and in all of ALS-D. TDP-43-positive glial inclusions were also found in 12 cases of cALS and in all of ALS-D. These TDP-43-positive neuronal and glial inclusions were more numerous in ALS-D than cALS. In ALS-D, neuronal loss in the substantia nigra was found in all the cases, whereas mild gliosis without obvious neuronal loss was noted in the neostriaum in only two cases. These findings suggest that the neostriatum is also involved in the disease process of ALS with and without dementia.     

Motor neuron disease clinically limited to the lower motor neuron is a diffuse TDP-43 proteinopathy

Motor neuron disease (MND) may present as an isolated lower motor neuron (LMN) disorder. Although the significance of pathological 43 kDa transactive responsive sequence DNA binding protein (TDP-43) for amyotrophic lateral sclerosis (ALS) was appreciated only recently, the topographical distribution of TDP-43 pathology in MND clinically isolated to the LMN versus normal controls (COs) is only incompletely described. Therefore, we performed longitudinal clinical evaluation and retrospective chart review of autopsied patients diagnosed with isolated LMN disease. Cases with a disease duration over 4 years were designated as progressive muscular atrophy (PMA), and those with a more rapid course as MND/LMN. Immunohistochemistry was employed to identify neuronal and glial TDP-43 pathology in the central nervous system (CNS) in patients and COs. We examined 19 subjects including six patients (i.e., four with MND/LMN and two with PMA) and 13 COs. All patients showed significant TDP-43 linked degeneration of LMNs, and five cases showed a lesser degree of motor cortex degeneration. Additional brain areas were affected in varying degrees, ranging from predominantly brainstem pathology to significant involvement of the whole CNS including neocortical and limbic areas. Pathological TDP-43 was present only rarely in the CO group. We conclude that MND limited to the LMN and PMA is part of a disease continuum that includes ALS and FTLD-TDP, all of which are characterized by widespread TDP-43 pathology. Hence, we suggest that the next revision of the El Escorial criteria for the diagnosis of ALS include MND patients with disease clinically limited to the LMN and PMA as variants of ALS, which like classical ALS, are TDP-43 proteinopathies.     

Pathological TDP-43 in parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam

Pathological TDP-43 is the major disease protein in frontotemporal lobar degeneration characterized by ubiquitin inclusions (FTLD-U) with/without motor neuron disease (MND) and in amyotrophic lateral sclerosis (ALS). As Guamanian parkinsonism–dementia complex (PDC) or Guamanian ALS (G-PDC or G-ALS) of the Chamorro population may present clinically similar to FTLD-U and ALS, TDP-43 pathology may be present in the G-PDC and G-ALS. Thus, we examined cortical or spinal cord samples from 54 Guamanian subjects for evidence of TDP-43 pathology. In addition to cortical neurofibrillary and glial tau pathology, G-PDC was associated with cortical TDP-43 positive dystrophic neurites and neuronal and glial inclusions in gray and/or white matter. Biochemical analyses showed the presence of FTLD-U-like insoluble TDP-43 in G-PDC, but not in Guam controls (G-C). Spinal cord pathology of G-PDC or G-ALS was characterized by tau positive tangles as well as TDP-43 positive inclusions in lower motor neurons and glial cells. G-C had variable tau and negligible TDP-43 pathology. These results indicate that G-PDC and G-ALS are associated with pathological TDP-43 similar to FTLD-U with/without MND as well as ALS, and that neocortical or hippocampal TDP-43 pathology distinguishes controls from disease subjects better than tau pathology. Finally, we conclude that the spectrum of TDP-43 proteinopathies should be expanded to include neurodegenerative cognitive and motor diseases, affecting the Chamorro population of Guam. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. VM-YL is the John H. Ware III Chair of Alzheimer’s Research and JQT is the William Maul Measey-Truman G. Schnabel, Jr., MD, Professor of Geriatric Medicine and Gerontology.     

TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis

BACKGROUND: TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1). METHODS: TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identified variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families. FINDINGS: We identified two variants in TARDBP, which would encode Gly290Ala and Gly298Ser forms of TDP-43, in two kindreds with familial ALS. The variants seem to be pathogenic because they co-segregated with disease in both families, were absent in controls, and were associated with TDP-43 neuropathology in both members of one of these families for whom CNS tissue was available. INTERPRETATION: The Gly290Ala and Gly298Ser mutations are located in the glycine-rich domain of TDP-43, which regulates gene expression and mediates protein-protein interactions such as those with heterogeneous ribonucleoproteins. Owing to the varied and important cellular functions of TDP-43, these mutations might cause neurodegeneration through both gains and losses of function. The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U. FUNDING: National Institutes of Health (AG10124, AG17586, AG005136-22, PO1 AG14382), Department of Veterans Affairs, Friedrich-Baur Stiftung (0017/2007), US Public Health Service, ALS Association, and Fundació 'la Caixa'.     

Reappraisal of the anatomical spreading and propagation hypothesis about TDP-43 aggregation in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Neuronal inclusion of transactivation response DNA-binding protein 43 kDa (TDP-43) is known to be a pathologic hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43, which is physiologically a nuclear protein, is mislocalized from the nucleus and aggregated within the cytoplasm of affected neurons in ALS and FTLD patients. Neuropathologic or experimental studies have addressed mechanisms underlying spreading of TDP-43 inclusions in the central nervous system of ALS and FTLD patients. On the basis of postmortem observations, it is hypothesized that TDP-43 inclusions spread along the neural projections. A centrifugal gradient of TDP-43 pathology in certain anatomical systems and axonal or synaptic aggregation of TDP-43 may support the hypothesis. Experimental studies have revealed cell-to-cell propagation of aggregated or truncated TDP-43, which indicates a direct transmission of TDP-43 inclusions to contiguous cells. However, discrepancies remain between the cell-to-cell propagation suggested in the experimental models and the anatomical spreading of TDP-43 aggregations based on postmortem observations. Trans-synaptic transmission, rather than the direct cell-to-cell transmission, may be consistent with the anatomical spreading of TDP-43 aggregations, but cellular mechanisms of trans-synaptic transmission of aggregated proteins remain to be elucidated. Moreover, the spreading of TDP-43 inclusions varies among patients and genetic backgrounds, which indicates host-dependent factors for spreading of TDP-43 aggregations. Perturbation of cellular TDP-43 clearance may be a possible factor modifying the aggregation and spreading. This review discusses postmortem and experimental evidence that address mechanisms of spreading of TDP-43 pathology in the central nervous system of ALS and FTLD patients.     

Distinct TDP-43 pathology in ALS patients with ataxin 2 intermediate-length polyQ expansions

Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease characterized by degeneration of motor neurons, resulting in paralysis and death. A pathological hallmark of the degenerating motor neurons in most ALS patients is the presence of cytoplasmic inclusions containing the protein TDP-43. The morphology and type of TDP-43 pathological inclusions is variable and can range from large round Lewy body-like inclusions to filamentous skein-like inclusions. The clinical significance of this variable pathology is unclear. Intermediate-length polyglutamine (polyQ) expansions in ataxin 2 were recently identified as a genetic risk factor for ALS. Here we have analyzed TDP-43 pathology in a series of ALS cases with or without ataxin 2 intermediate-length polyQ expansions. The motor neurons of ALS cases harboring ataxin 2 polyQ expansions (n = 6) contained primarily skein-like or filamentous TDP-43 pathology and only rarely, if ever, contained large round inclusions, whereas the ALS cases without ataxin 2 polyQ expansions (n = 13) contained abundant large round and skein-like TDP-43 pathology. The paucity of large round TDP-43 inclusions in ALS cases with ataxin 2 polyQ expansions suggests a distinct pathological subtype of ALS and highlights the possibility for distinct pathogenic mechanisms.     

Molecular link between inefficient GluA2 RNA editing and TDP-43 pathology in ALS motor neurons

The motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients exhibit several molecular abnormalities, including 2 that are specific to ALS motor neurons: (1) pathological changes related to the mislocalization of the TAR DNA-binding protein (TDP-43), including both the appearance of phosphorylated TDP-43-containing inclusions in the cytoplasm and the loss of TDP-43 from the nucleus; and (2) inefficient RNA editing at the Q/R site of GluA2, a subunit of the AMPA receptor. TDP-43-related pathological features are closely associated with ALS in most ALS patients and with significant behavioral and pathological changes in genetically engineered mice; therefore, abnormal TDP-43 processing is believed to play a role in the pathogenesis of ALS. The extent of GluA2 RNA editing decreases in the motor neurons of sporadic ALS patients in a disease-specific and motor neuron-selective manner. Importantly, this molecular abnormality is a direct cause of death of motor neurons in conditional knockout mice for adenosine deaminase acting on RNA 2 (ADAR2), the enzyme that specifically catalyzes RNA editing at the GluA2 Q/R site. Notably, these molecular abnormalities, i.e., TDP-43-related pathological features and inefficient GluA2 RNA editing, are found in approximately half of the motor neurons in sporadic ALS patients and both of them always occur in the same motor neurons. Because TDP-43-related pathological features and inefficient GluA2 RNA editing are highly disease specific in ALS motor neurons, investigation into the molecular link between these abnormalities is likely to provide new insights into ALS pathogenesis.