کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8841459 | 1615021 | 2018 | 21 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics
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کلمات کلیدی
CCCPND6MFN2hnRNPND3TDP-43C30Drp1VDAC1MNDN27APPPHB2prohibitin 2APP/PS1 - APP / PS1presenilin 1 - Presenilin 1amyotrophic lateral sclerosis - اسکلروز جانبی آمیوتروفیکAlzheimer disease - بیماری آلزایمرALS - بیماری اسکلروز جانبی آمیوتروفیکmotor neuron disease - بیماری نورون حرکتیheterogeneous nuclear ribonucleoprotein - ریبونولوپروتئین ناهمگن هسته ایMitophagy - میتوفاژیmitofusin 2 - میتوفوسین 2Mitochondria - میتوکندریاdynamin-related protein 1 - پروتئین مرتبط با دینام 1amyloid precursor protein - پروتئین پیش ماده آمیلوئیcarbonyl cyanide m-chlorophenyl hydrazine - کربونیل سیانید m-کلروفنیل هیدرازین
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
علوم اعصاب (عمومی)
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics](/preview/png/8841459.png)
چکیده انگلیسی
Transactive response DNA-binding protein of 43â¯kDa (TDP-43) functions as a heterogeneous nuclear ribonucleoprotein and is the major pathological protein in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). TDP-43 pathology may also be present as a comorbidity in approximately 20-50% of sporadic Alzheimer's disease cases. In a mouse model of MND, full-length TDP-43 increases association with the mitochondria and blocking the TDP-43/mitochondria interaction ameliorates motor dysfunction. Utilizing a proteomics screen, several mitochondrial TDP-43-interacting partners were identified, including voltage-gated anion channel 1 (VDAC1) and prohibitin 2 (PHB2), a crucial mitophagy receptor. Overexpression of TDP-43 led to an increase in PHB2 whereas TDP-43 knockdown reduced PHB2 expression in cells treated with carbonyl cyanide m-chlorophenylhydrazone (CCCP), an inducer of mitophagy. These results suggest that TDP-43 expression contributes to metabolism and mitochondrial function however we show no change in bioenergetics when TDP-43 is overexpressed and knocked down in HEK293T cells. Furthermore, the fusion protein mitofusin 2 (MFN2) interacts in complex with TDP-43 and selective expression of human TDP-43 in the hippocampus and cortex induced an age-dependent change in Mfn2 expression. Mitochondria morphology is altered in 9-month-old mice selectively expressing TDP-43 in an APP/PS1 background compared with APP/PS1 littermates. We further confirmed TDP-43 localization to the mitochondria using immunogold labeled TDP-43 transmission electron microscopy (TEM) and mitochondrial isolation methods There was no increase in full-length TDP-43 localized to the mitochondria in APP/PS1 mice compared to wild-type (littermates); however, using C- and N-terminal-specific TDP-43 antibodies, the N-terminal (27â¯kDa, N27) and C-terminal (30â¯kDa, C30) fragments of TDP-43 are greatly enriched in mitochondrial fractions. In addition, when the mitochondrial peptidase (PMPCA) is overexpressed there is an increase in the N-terminal fragment (N27). These results suggest that TDP-43 processing may contribute to metabolism and mitochondrial function.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neuroscience Letters - Volume 678, 21 June 2018, Pages 8-15
Journal: Neuroscience Letters - Volume 678, 21 June 2018, Pages 8-15
نویسندگان
Stephani A. Davis, Sheed Itaman, Christopher M. Khalid-Janney, Justin A. Sherard, James A. Dowell, Nigel J. Cairns, Michael A. Gitcho,