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BACKGROUND AND PURPOSE: The role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the NOTCH2NLC GGC repeat expansions in a large cohort of patients with PD. We also investigate the role of GGC repeat expansions within NOTCH2NLC in the dopaminergic neurodegeneration of SN. METHODS: A total of 2,522 patients diagnosed with PD and 1,085 health controls were analyzed for the repeat expansions of NOTCH2NLC by repeat-primed PCR and GC-rich PCR assay. Furthermore, the effects of GGC repeat expansions in NOTCH2NLC on dopaminergic neurons were investigated by using recombinant adeno-associated virus (AAV)-mediated overexpression of NOTCH2NLC with 98 GGC repeats in the SN of mice by stereotactic injection. RESULTS: Four PD pedigrees (4/333, 1.2%) and three sporadic PD patients (3/2189, 0.14%) were identified with pathogenic GGC repeat expansions (larger than 60 GGC repeats) in the NOTCH2NLC gene, while eight PD patients and one healthy control were identified with intermediate GGC repeat expansions ranging from 41 to 60 repeats. No significant difference was observed in the distribution of intermediate NOTCH2NLC GGC repeat expansions between PD cases and controls (Fisher's exact test p-value = 0.29). Skin biopsy showed P62-positive intranuclear NOTCH2NLC-polyGlycine (polyG) inclusions in the skin nerve fibers of patient. Expanded GGC repeats in NOTCH2NLC produced widespread intranuclear and perinuclear polyG inclusions, which led to a severe loss of dopaminergic neurons in the SN. Consistently, polyG inclusions were presented in the SN of EIIa-NOTCH2NLC-(GGC)98 transgenic mice and also led to dopaminergic neuron loss in the SN. CONCLUSIONS: Overall, our findings provide strong evidence that GGC repeat expansions within NOTCH2NLC contribute to the pathogenesis of PD and cause degeneration of nigral dopaminergic neurons.
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Doença de Parkinson , Animais , Humanos , Camundongos , Neurônios Dopaminérgicos/patologia , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/patologia , Camundongos Transgênicos , Degeneração Neural/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Substância Negra/patologia , Expansão das Repetições de TrinucleotídeosRESUMO
Huntington disease (HD) is an ideal model for investigating selective neurodegeneration, as expanded polyQ repeats in the ubiquitously expressed huntingtin (HTT) cause the preferential neurodegeneration in the striatum of the HD patient brains. Here we report that adeno-associated virus (AAV) transduction-mediated depletion of Hap1, the first identified huntingtin-associated protein, in adult HD knock-in (KI) mouse brains leads to selective neuronal loss in the striatum. Further, Hap1 depletion-mediated neuronal loss via AAV transduction requires the presence of mutant HTT. Rhes, a GTPase that is enriched in the striatum and sumoylates mutant HTT to mediate neurotoxicity, binds more N-terminal HTT when Hap1 is deficient. Consistently, more soluble and sumoylated N-terminal HTT is presented in HD KI mouse striatum when HAP1 is absent. Our findings suggest that both Rhes and Hap1 as well as cellular stress contribute to the preferential neurodegeneration in HD, highlighting the involvement of multiple factors in selective neurodegeneration.
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Corpo Estriado/patologia , Doença de Huntington/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , Optogenética , Animais , Corpo Estriado/metabolismo , Dependovirus , Regulação da Expressão Gênica , Doença de Huntington/genética , Lasers , Luz , Camundongos , Rede Nervosa , Proteínas do Tecido Nervoso/genéticaRESUMO
Demyelination is a common pathological feature of a large number of neurodegenerative diseases including multiple sclerosis and Huntington's disease (HD). Laquinimod (LAQ) has been found to have therapeutic effects on multiple sclerosis and HD. However, the mechanism underlying LAQ's therapeutic effects remains unknown. Using HD mice that selectively express mutant huntingtin in oligodendrocytes and show demyelination, we found that LAQ reduces the Ser259 phosphorylation on myelin regulatory factor (MYRF), an oligodendrocyte-specific transcription factor promoting the expression of myelin-associated genes. The reduced MYRF phosphorylation inhibits MYRF's binding to mutant huntingtin and increases the expression of myelin-associated genes. We also found that PRKG2, a cGMP-activated protein kinase subunit II, promotes the Ser259-MYRF phosphorylation and that knocking down PRKG2 increased myelin-associated protein's expression in HD mice. Our findings suggest that PRKG2-regulated phosphorylation of MYRF is involved in demyelination and can serve as a potential therapeutic target for reducing demyelination.
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Doença de Huntington , Animais , Doença de Huntington/genética , Camundongos , Bainha de Mielina/metabolismo , Oligodendroglia , Fosforilação , Fatores de Transcrição/metabolismoRESUMO
A heterozygous frameshift PRRT2 mutation (c.649_650InsC) has been identified as the major causative mutation in several paroxysmal disorders, including paroxysmal kinesigenic dyskinesia (PKD). Since PKD is an autosomal dominant disorder and since the frameshift mutations of PRRT2 may create a truncated protein, it remains unclear whether this mutation causes toxic gain of function or loss of function. By generating Prrt2 knock-in (KI) mice that express human PRRT2 with the c.649_650InsC mutation and by comparing the phenotypes of Prrt2 KI mice with knockout (KO) mice, we find that both KI and KO mice show the same extents of impaired rotarod and balance beam performance as well as the same sensitivity to seizure induction. Both KI and KO mice show altered formation of SNARE complex and number of synaptic vesicles. In addition, western blotting of KI mouse brain tissues could not detect truncated PRRT2 protein that might be generated by the c.649_650InsC mutation. Moreover, the level of PRRT2 mRNA in KI mice is significantly decreased, recapitulating the reduction of PRRT2 mRNA reported in PKD patients. Furthermore, mutant PRRT2 mRNA is unstable and showed shortened half-life than wild-type PRRT2 mRNA. Our studies suggest that PRRT2 frameshift mutation leads to the loss of function by affecting its mRNA stability, a mechanism that is different from haploinsufficiency due to dysfunctional protein or gain of function caused by truncated protein.
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Distonia/genética , Mutação da Fase de Leitura , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/genética , Animais , Distonia/patologia , Técnicas de Introdução de Genes , Humanos , Mutação com Perda de Função , Camundongos , Camundongos Knockout , RNA Mensageiro/químicaRESUMO
Autism is a childhood neurodevelopmental disorder with high heterogeneity. Following our genome-wide associated loci with autism, we performed sequencing analysis of the coding regions, UTR and flanking splice junctions of AMPD1 in 830 Chinese autism individuals as well as 514 unrelated normal controls. Fourteen novel variants in the coding sequence were identified, including 11 missense variants and 3 synonymous mutations. Among these missense variants, 10 variants were absent in 514 control subjects, and conservative and functional prediction was carried out. Mitochondria activity and lactate dehydrogenase assay were performed in 5 patients' lymphoblast cell lines; p.P572S and p.S626C showed decreased mitochondrial complex I activity, and p.S626C increased lactate dehydrogenase release in medium. Conclusively, our data suggested that mutational variants in AMPD1 contribute to autism risk in Han Chinese population, uncovering the contribution of mutant protein to disease development that operates via mitochondria dysfunction and cell necrosis.
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AMP Desaminase/genética , Povo Asiático/genética , Transtorno Autístico/genética , Transtorno Autístico/metabolismo , L-Lactato Desidrogenase/metabolismo , Mitocôndrias/metabolismo , Adolescente , Linhagem Celular , Criança , Pré-Escolar , China , Feminino , Humanos , Masculino , Mutação/genéticaRESUMO
BACKGROUND: High myopia, with the characteristic feature of refractive error, is one of the leading causes of blindness worldwide. It has a high heritability, but only a few causative genes have been identified and the pathogenesis is still unclear. METHODS: We used whole genome linkage and exome sequencing to identify the causative mutation in a non-syndromic high myopia family. Direct Sanger sequencing was used to screen the candidate gene in additional sporadic cases or probands. Immunofluorescence was used to evaluate the expression pattern of the candidate gene in the whole process of eye development. Real-time quantitative PCR and immunoblot was used to investigate the functional consequence of the disease-associated mutations. RESULTS: We identified a nonsense mutation (c.141C>G:p.Y47*) in SLC39A5 co-segregating with the phenotype in a non-syndromic severe high myopia family. The same nonsense mutation (c.141C>G:p.Y47*) was detected in a sporadic case and a missense mutation (c.911T>C:p.M304T) was identified and co-segregated in another family by screening additional cases. Both disease-associated mutations were not found in 1276 control individuals. SLC39A5 was abundantly expressed in the sclera and retina across different stages of eye development. Furthermore, we found that wild-type, but not disease-associated SLC39A5 inhibited the expression of Smadl, a key phosphate protein in the downstream of the BMP/TGF-ß (bone morphogenic protein/transforming growth factor-ß) pathway. CONCLUSIONS: Our study reveals that loss-of-function mutations of SLC39A5 are associated with the autosome dominant non-syndromic high myopia, and interference with the BMP/TGF-ß pathway may be one of the molecular mechanisms for high myopia.
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Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas de Transporte de Cátions/genética , Miopia/genética , Fator de Crescimento Transformador beta/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas de Transporte de Cátions/metabolismo , Criança , Pré-Escolar , Embrião de Mamíferos/química , Olho/química , Olho/crescimento & desenvolvimento , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Camundongos , Mutação/genética , Linhagem , Fator de Crescimento Transformador beta/genéticaRESUMO
Introduction: Huntington's disease (HD) is caused by CAG trinucleotide repeats in the HTT gene. Selective neurodegeneration in the striatum is prominent in HD, despite widespread expression of mutant HTT (mHTT). Ras homolog enriched in the striatum (Rhes) is a GTP-binding protein enriched in the striatum, involved in dopamine-related behaviors and autophagy regulation. Growing evidence suggests Rhes plays a critical role in the selective striatal degeneration in HD, but its specific function in this context remains complex and controversial. Methods: In this study, we utilized CRISPR/Cas9 to knockdown Rhes at different disease stages through adeno-associated virus (AAV) transduction in HD knock-in (KI) mice. Immunoblotting and immunofluorescence were employed to assess the impact of Rhes depletion on mHTT levels, neuronal loss, astrogliosis and autophagy activity. Results: Rhes depletion in 22-week-old HD KI mice (representing the presymptomatic stage) led to mHTT accumulation, reduced neuronal cell staining, and increased astrogliosis. However, no such effects were observed in 36-week-old HD KI mice (representing the symptomatic stage). Additionally, Rhes deletion in 22-week-old HD KI mice resulted in increased P62 levels, reduced LC3-II levels, and unchanged phosphorylation of mTOR and beclin-1, unchanged mTOR protein level, except for a decrease in beclin-1. Discussion: Our findings suggest that knockdown Rhes promotes striatal aggregation of mutant huntingtin by reducing autophagy activity in a mTOR-independent manner. Rhes plays a protective role during the presymptomatic stage of HD KI mice.
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BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized by widespread intranuclear inclusions in the nervous system as well as multiple visceral organs. In 2019, expanded GGC repeats within the 5' untranslated region of the NOTCH2NLC gene was identified as the causative factor. NIID is a heterogeneous disorder with variable clinical manifestations including cognitive impairment, cerebellar ataxia, parkinsonism, paroxysmal symptoms, autonomic dysfunction, and muscle weakness. Although NIID primarily affects the central and peripheral nervous systems, growing evidence suggests potential cardiac abnormalities in NIID. However, the link between expanded GGC repeats within NOTCH2NLC and cardiac dysfunction remains uncertain. RESULTS: In this study, we utilized two transgenic mouse models, expressing NOTCH2NLC-(GGC)98 ubiquitously or specifically in cardiomyocytes, and identified p62 (also known as sequestosome 1, SQSTM1)-positive intranuclear NOTCH2NLC-polyG inclusions in cardiomyocytes in two mouse models. We observed that both models exhibited cardiac-related pathological and echocardiographic changes, albeit exhibiting varying degrees of severity. Transcriptomic analysis revealed shared downregulation of genes related to ion channels and mitochondria in both models, with the cardiomyocyte-specific mice showing a more pronounced downregulation of mitochondria and energy metabolism-related pathways. Further investigations revealed decreased expression of mitochondria-related genes and electron transport chain activity. At last, we conducted a retrospective review of cardiac-related examination results from NIID patients at our hospital and also identified some cardiac abnormalities in NIID patients. CONCLUSIONS: Our study provided the first in vivo evidence linking GGC repeat expansions within NOTCH2NLC to cardiac abnormalities and highlighted the contribution of mitochondrial dysfunction in the development of cardiac abnormalities.
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Vanishing white matter disease (VWM) is one of the most common childhood inherited leukoencephalopathies with autosomal recessive inheritance. Mutations in five genes, EIF2B1-5, have been identified as the major cause of VWM. In this study, a targeted gene capture sequencing panel comprising 160 known pathogenic genes associated with leukoencephalopathies was performed in a large Han Chinese family affected by adult-onset VWM, and a novel heterozygous missense mutation (c.1337G > A [p. R446H]) in EIF2B4 (NM_001034116.2) was detected. Further functional studies in HEK 293 cells showed dramatically reduced EIF2Bδ protein levels in the mutated group compared with the wild-type group. This study revealed that a heterozygous missense mutation (c.1337G > A [p. R446H]) in EIF2B4 was potentially associated with the adult-onset mild phenotype of VWM. In contrast to previous reports, autosomal dominant inheritance was also observed in adult-onset VWM.
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GGC repeat expansions within NOTCH2NLC have been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). To understand the molecular pathogenesis of NIID, here, we established both a transgenic mouse model and a human neural progenitor cells (hNPCs) model. Expression of the NOTCH2NLC with expanded GGC repeats produced widespread intranuclear and perinuclear polyglycine (polyG), polyalanine (polyA), and polyarginine (polyR) inclusions, leading to behavioral deficits and severe neurodegeneration, which faithfully mimicked the clinical and pathological features associated with NIID. Furthermore, conserved alternative splicing events were identified between the NIID mouse and hNPC models, among which was the enrichment of the binding motifs of hnRNPM, an RNA binding protein known as alternative splicing regulator. Expanded NOTCH2NLC-polyG and NOTCH2NLC-polyA could interact with and sequester hnRNPM, while overexpression of hnRNPM could ameliorate the cellular toxicity. These results together suggested that dysfunction of hnRNPM could play an important role in the molecular pathogenesis of NIID.
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Corpos de Inclusão Intranuclear , Doenças Neurodegenerativas , Animais , Humanos , Camundongos , Modelos Animais de Doenças , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/patologia , Doenças Neurodegenerativas/genética , Proteínas de Ligação a RNARESUMO
Selective neuronal accumulation of misfolded proteins is a key step toward neurodegeneration in a wide range of neurodegenerative diseases, including Huntington's (HD) diseases. Our recent studies suggest that Hsp70-binding protein 1 (HspBP1), an Hsp70/CHIP inhibitor that reduces protein folding, is highly expressed in neuronal cells and accounts for the accumulation of the HD protein huntingtin (HTT) in neuronal cells. To further determine the role of HspBP1 in regulation of mutant protein accumulation, we investigated whether increasing expression of HspBP1 in glial cells can also induce the accumulation of endogenous mutant HTT in glial cells and yield non-cell-autonomous toxic effects. We performed stereotaxic injection of AAV to selectively express HspBP1 in astrocytes in the brains of HD140Q knock-in (KI) mice that express mutant HTT ubiquitously but do not display obvious neurodegeneration. However, HspBP1 expression in HD140Q astrocytes led to the increased accumulation of endogenous mutant HTT and robust neuronal loss in the striatum of HD140Q KI mice. In transgenic HD mice that selectively express mutant HTT in astrocytes, increased accumulation of mutant HTT in astrocytes via HspBP1 expression did not elicit neurodegeneration but could exacerbate neurological symptoms. Consistently, suppressing the expression of endogenous HspBp1 in the striatum of HD140Q KI mice via CRISPR/Cas9 led to a significant reduction of mutant HTT accumulation. Our findings suggest that although endogenous mutant HTT in astrocytes can exacerbate neurological symptoms, it mediates neurodegeneration only when mutant HTT is also accumulated in neuronal cells.
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Astrócitos/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Doença de Huntington/metabolismo , Mutação/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Astrócitos/patologia , Células Cultivadas , Feminino , Doença de Huntington/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Fresnel micro-structured lenses are widely used in the field of modern optoelectronic technology. High-precision Fresnel micro-structured mold is the key technology to achieve its large-scale replication production. Focusing on the surface waviness error of Fresnel micro-structured mold machined by parallel grinding process, this paper conducted theoretical modeling and experiment research. Based on the grinding kinematics theory, the simulation models of the surface waviness topography and the circular waviness profiles of the ground Fresnel micro-structured mold were developed, considering the combined influence of the non-integer rotation speed ratio and other grinding parameters. A series of grinding experiments were carried out to verify the proposed simulation models. The influence of a non-integer rotation speed ratio and a wave-shift value upon the surface waviness error of the ground Fresnel micro-structured molds were analyzed. Both the simulation and experimental results proved that choosing the non-integer rotation speed ratio and a proper wave-shift value could greatly reduce the surface waviness error and improve the surface quality and uniformity.
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Huntingtin-associated protein 1 (Hap1) was initially identified as a brain-enriched protein that binds to the Huntington's disease protein, huntingtin. Unlike huntingtin that is ubiquitously expressed in the brain, Hap1 is enriched in the brain with the highest expression level in the hypothalamus. The selective enrichment of Hap1 in the hypothalamus suggests that Hap1 may play a specific role in hypothalamic function that can regulate metabolism and stress response. Here we report that Hap1 is colocalized and interacts with the glucocorticoid receptor (GR) in mouse hypothalamic neurons. Genetic depletion of Hap1 reduced the expression level of GR in the hypothalamus. Dexamethasone, a GR agonist, treatment or fasting of mice induced stress, resulting in increased expression of Hap1 in the hypothalamus. However, when Hap1 was absent, these treatments promoted GR reduction in the hypothalamus. In cultured cells, loss of Hap1 shortened the half-life of GR. These findings suggest that Hap1 stabilizes GR in the cytoplasm and that Hap1 dysfunction or deficiency may alter animal's stress response.
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A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-19873-9.
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Polyglutamine expansion in proteins can cause selective neurodegeneration, although the mechanisms are not fully understood. In Huntington's disease (HD), proteolytic processing generates toxic N-terminal huntingtin (HTT) fragments that preferentially kill striatal neurons. Here, using CRISPR/Cas9 to truncate full-length mutant HTT in HD140Q knock-in (KI) mice, we show that exon 1 HTT is stably present in the brain, regardless of truncation sites in full-length HTT. This N-terminal HTT leads to similar HD-like phenotypes and age-dependent HTT accumulation in the striatum in different KI mice. We find that exon 1 HTT is constantly generated but its selective accumulation in the striatum is associated with the age-dependent expression of striatum-enriched HspBP1, a chaperone inhibitory protein. Our findings suggest that tissue-specific chaperone function contributes to the selective neuropathology in HD, and highlight the therapeutic potential in blocking generation of exon 1 HTT.
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Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/etiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fatores Etários , Animais , Sistemas CRISPR-Cas , Núcleo Celular/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Éxons , Feminino , Técnicas de Introdução de Genes , Doença de Huntington/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , FenótipoRESUMO
Spinocerebellar ataxias 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP). The selective neurodegeneration in the cerebellum in SCA17 raises the question of why ubiquitously expressed polyQ proteins can cause neurodegeneration in distinct brain regions in different polyQ diseases. By expressing mutant TBP in different brain regions in adult wild-type mice via stereotaxic injection of adeno-associated virus, we found that adult cerebellar neurons are particularly vulnerable to mutant TBP. In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated gene transcription to down-regulate INPP5A, a protein that is highly abundant in the cerebellum. CRISPR/Cas9-mediated deletion of Inpp5a in the cerebellum of wild-type mice leads to Purkinje cell degeneration, and Inpp5a overexpression decreases inositol 1,4,5-trisphosphate (IP3) levels and ameliorates Purkinje cell degeneration in SCA17 knock-in mice. Our findings demonstrate the important contribution of a tissue-specific protein to the polyQ protein-mediated selective neuropathology.
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Inositol Polifosfato 5-Fosfatases/genética , Células de Purkinje/patologia , Ataxias Espinocerebelares/patologia , Proteína de Ligação a TATA-Box/genética , Animais , Modelos Animais de Doenças , Regulação para Baixo , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Inositol 1,4,5-Trifosfato/metabolismo , Inositol Polifosfato 5-Fosfatases/metabolismo , Camundongos , Camundongos Transgênicos , Peptídeos/genética , Peptídeos/metabolismo , Células de Purkinje/metabolismo , Fator de Transcrição Sp1/metabolismo , Ataxias Espinocerebelares/genética , Proteína de Ligação a TATA-Box/metabolismo , Expansão das Repetições de TrinucleotídeosRESUMO
Spinocerebellar ataxia type 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP), which functions as a general transcription factor. Like other polyQ expansion-mediated diseases, SCA17 is characterized by late-onset and selective neurodegeneration, despite the disease protein being ubiquitously expressed in the body. To date, the pathogenesis of polyQ diseases is not fully understood, and there are no effective treatments for these devastating disorders. The well-characterized function of TBP and typical neurodegeneration in SCA17 give us opportunities to understand how polyQ expansion causes selective neurodegeneration and to develop effective therapeutics. In this review, we discuss the molecular mechanisms behind SCA17, focusing on transcriptional dysregulation as its major cause. Mounting evidence suggests that reversing transcriptional alterations induced by mutant TBP and reducing the expression of mutant TBP are promising strategies to treat SCA17.
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Modelos Animais de Doenças , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/terapia , Proteína de Ligação a TATA-Box/genética , Transcrição Gênica/fisiologia , Expansão das Repetições de Trinucleotídeos/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Terapia Genética/métodos , Terapia Genética/tendências , Humanos , Ataxias Espinocerebelares/metabolismo , Proteína de Ligação a TATA-Box/metabolismoRESUMO
In order to explore the possibility to predict the risk factors for postoperative complications and survival time, the clinical data of 152 patients (including 116 males and 36 females) who had undergone neo-adjuvant therapy and surgery for stage IIIA and B non-small cell lung cancer (NSCLC) were retrospectively analyzed. Demographic data, preoperative functional parameters, staging, induction regimen (chemotherapy alone or associated with radiotherapy), associated disorders, and data about operation were collected. Chi-square test and multivariate analysis fitting the unconditional logistic regression model were performed to identify predictors of postoperative complications, while Kaplan-Meier and multivariate Cox proportional hazard model were employed to identify predictors of survival time, respectively. The univariate analysis demonstrated that forced expiratory volume in 1 second predicted percent (FEV1%, P=0.040) and associated disorders (P=0.020) were the predictive factors of complications, but multivariate analysis found no independence factors (P>0.05) of it. Univariate Kaplan-Meier analysis showed that stage (P=0.050) and pneumonectomy (P=0.018) affected the survival time. However, multivariate Cox proportional hazard model analysis demonstrated that only pneumonectomy (P=0.026) was associated with a decreased survival time, but no differences between right and left pneumonectomy were found. The results suggest that the risk factor for postoperative complications is acceptable, and pneumonectomy is associated with increased mortality, which should be performed only in stage III NSCLC patients.