Language:

Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice

Neurobiology of disease, 2021-07, Vol.154, p.105359-105359, Article 105359 [Peer Reviewed Journal]

2021 The Authors ;Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved. ;ISSN: 0969-9961 ;EISSN: 1095-953X ;DOI: 10.1016/j.nbd.2021.105359 ;PMID: 33798740

Full text available

Citations Cited by

Actions
1. Add to My Research
2. Remove from My Research
3. E-mail
4. Print
5. Permalink
6. Citation
7. EasyBib
8. EndNote
9. RefWorks
10. Delicious
11. Export RIS
12. Export BibTeX

Title:
Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice
Author: Perera, Nirma D. ; Tomas, Doris ; Wanniarachchillage, Nayomi ; Cuic, Brittany ; Luikinga, Sophia J. ; Rytova, Valeria ; Turner, Bradley J.
Subjects: ALS ; Amyotrophic Lateral Sclerosis - chemically induced ; Amyotrophic Lateral Sclerosis - genetics ; Amyotrophic Lateral Sclerosis - metabolism ; Animals ; Antihypertensive Agents - toxicity ; Autophagy ; Autophagy - physiology ; DNA-Binding Proteins - biosynthesis ; DNA-Binding Proteins - genetics ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitophagy - physiology ; Motor neuron ; Phenotype ; Rilmenidine ; Rilmenidine - toxicity ; TDP-43 ; TOR Serine-Threonine Kinases - biosynthesis ; TOR Serine-Threonine Kinases - genetics
Is Part Of: Neurobiology of disease, 2021-07, Vol.154, p.105359-105359, Article 105359
Description: Autophagy, which mediates the delivery of cytoplasmic substrates to the lysosome for degradation, is essential for maintaining proper cell homeostasis in physiology, ageing, and disease. There is increasing evidence that autophagy is defective in neurodegenerative disorders, including motor neurons affected in amyotrophic lateral sclerosis (ALS). Restoring impaired autophagy in motor neurons may therefore represent a rational approach for ALS. Here, we demonstrate autophagy impairment in spinal cords of mice expressing mutant TDP-43Q331K or co-expressing TDP-43WTxQ331K transgenes. The clinically approved anti-hypertensive drug rilmenidine was used to stimulate mTOR-independent autophagy in double transgenic TDP-43WTxQ331K mice to alleviate impaired autophagy. Although rilmenidine treatment induced robust autophagy in spinal cords, this exacerbated the phenotype of TDP-43WTxQ331K mice, shown by truncated lifespan, accelerated motor neuron loss, and pronounced nuclear TDP-43 clearance. Importantly, rilmenidine significantly promoted mitophagy in spinal cords TDP-43WTxQ331K mice, evidenced by reduced mitochondrial markers and load in spinal motor neurons. These results suggest that autophagy induction accelerates the phenotype of this TDP-43 mouse model of ALS, most likely through excessive mitochondrial clearance in motor neurons. These findings also emphasise the importance of balancing autophagy stimulation with the potential negative consequences of hyperactive mitophagy in ALS and other neurodegenerative diseases. •Autophagy is impaired in spinal cords of transgenic TDP-43Q331K and TDP-43WTxQ331K mice•Rilmenidine stimulates efficient autophagy in spinal cords of TDP-43WTxQ331K mice•Rilmenidine induced mitophagy in spinal cords of TDP-43WTxQ331K mice associates with increased disease severity
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0969-9961
EISSN: 1095-953X
DOI: 10.1016/j.nbd.2021.105359
PMID: 33798740
Source: MEDLINE
DOAJ Directory of Open Access Journals

Back to results list


INSPIRE LIBRARY - TON DUC THANG UNIVERSITY	(84-028) 37 755 057	Feedback
19 Nguyen Huu Tho St. Dist.7, HCM	thuvien@tdtu.edu.vn	Feedback

Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice

2021 The Authors ;Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved. ;ISSN: 0969-9961 ;EISSN: 1095-953X ;DOI: 10.1016/j.nbd.2021.105359 ;PMID: 33798740

Searching Remote Databases, Please Wait