Universität zu Köln

Rumyantseva, Anastasia ORCID: 0000-0002-7847-6178 (2021). Loss of CLPP Ameliorates Consequences of DARS2 Depletion in Neurons. PhD thesis, Universität zu Köln.

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Abstract

Mitochondria are epicentres of neuronal metabolic and signalling pathways. Unsurprisingly, mitochondrial dysfunction, commonly presented as a reduction in OXPHOS, is a feature accompanying almost all neurodegenerative diseases. Mitochondrial diseases are a group of clinically, genetically, and biochemically heterogeneous disorders, arising from the dysfunctional respiratory chain. In most cases, mitochondrial diseases deteriorate life quality severely and are associated with high mortality. The tremendous progress made in the understanding of the genetic basis of mitochondrial diseases, however, is not matched by a breakthrough in therapeutic strategies. Disappointingly, conventional therapy for mitochondrial diseases offers only a modest curative effect. Patients are often treated with vitamin cocktails, intended to merely curb symptoms, or subjected to palliative care, emphasising the demand of novel therapeutic approaches. Intriguingly, we have previously discovered that devastating cardiomyopathy symptoms caused by the mitochondrial aspartyl-t-RNA synthetase (DARS2) deficiency can be ameliorated by the concomitant loss of mitochondrial matrix CLP protease proteolytic subunit (CLPP). In this study, we aimed to explore a possibility of CLPP targeting to alleviate neurodegeneration in two distinct models of mitochondrial encephalopathy. To this end, we employed newly generated Purkinje-cell specific DARS2-deficient mice and previously described forebrain neurons specific DARS2 knockout mice. To tackle the potential bias of targeting only one neuronal population, we generated double KOs for both models. xviii Here, we showed that the loss of CLPP is beneficial in both models of mitochondrial encephalopathy, driven by Dars2-deficiency. Importantly, we demonstrated that CLPP ablation delays neurodegeneration in several brain regions, including Purkinje cell layer, retrosplenial cortex and hippocampus. The reduced neuroinflammation and neurodegeneration significantly improved motor performance of mice highlighting the therapeutic potential of the CLPP targeting.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Rumyantseva, Anastasia anastasia.rumyantseva@uk-koeln.de orcid.org/0000-0002-7847-6178 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-456951
Date:	15 April 2021
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Natural sciences and mathematics
Uncontrolled Keywords:	Keywords Language Mitochondria English Neurodegeneration English Leukoencephalopathy English
Date of oral exam:	19 February 2021
Referee:	Name Academic Title Trifunovic, Aleksandra Prof.Dr. Villchez, David Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/45695