Universität zu Köln

Murru, Sara, Hess, Simon, Barth, Esther, Almajan, Eva R., Schatton, Desiree, Hermans, Steffen, Brodesser, Susanne, Langer, Thomas, Kloppenburg, Peter and Rugarli, Elena, I ORCID: 0000-0002-5782-1067 (2019). Astrocyte-specific deletion of the mitochondrial m-AAA protease reveals glial contribution to neurodegeneration. Glia, 67 (8). S. 1526 - 1542. HOBOKEN: WILEY. ISSN 1098-1136

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Abstract

Mitochondrial dysfunction causes neurodegeneration but whether impairment of mitochondrial homeostasis in astrocytes contributes to this pathological process remains largely unknown. The m-AAA protease exerts quality control and regulatory functions crucial for mitochondrial homeostasis. AFG3L2, which encodes one of the subunits of the m-AAA protease, is mutated in spinocerebellar ataxia SCA28 and in infantile syndromes characterized by spastic-ataxia, epilepsy and premature death. Here, we investigate the role of Afg3l2 and its redundant homologue Afg3l1 in the Bergmann glia (BG), radial astrocytes of the cerebellum that have functional connections with Purkinje cells (PC) and regulate glutamate homeostasis. We show that astrocyte-specific deletion of Afg3l2 in the mouse leads to late-onset motor impairment and to degeneration of BG, which display aberrant morphology, altered expression of the glutamate transporter EAAT2, and a reactive inflammatory signature. The neurological and glial phenotypes are drastically exacerbated when astrocytes lack both Afg31l and Afg3l2, and therefore, are totally depleted of the m-AAA protease. Moreover, mitochondrial stress responses and necroptotic markers are induced in the cerebellum. In both mouse models, targeted BG show a fragmented mitochondrial network and loss of mitochondrial cristae, but no signs of respiratory dysfunction. Importantly, astrocyte-specific deficiency of Afg3l1 and Afg3l2 triggers secondary morphological degeneration and electrophysiological changes in PCs, thus demonstrating a non-cell-autonomous role of glia in neurodegeneration. We propose that astrocyte dysfunction amplifies both neuroinflammation and glutamate excitotoxicity in patients carrying mutations in AFG3L2, leading to a vicious circle that contributes to neuronal death.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Murru, Sara UNSPECIFIED UNSPECIFIED UNSPECIFIED Hess, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Barth, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Almajan, Eva R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schatton, Desiree UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermans, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Brodesser, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Langer, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kloppenburg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Rugarli, Elena, I UNSPECIFIED orcid.org/0000-0002-5782-1067 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-134379
DOI:	10.1002/glia.23626
Journal or Publication Title:	Glia
Volume:	67
Number:	8
Page Range:	S. 1526 - 1542
Date:	2019
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1098-1136
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INTEGRATED STRESS-RESPONSE; GLUTAMATE TRANSPORTER; SPASTIC PARAPLEGIA; AFG3L2; ATAXIA; NECROPTOSIS; CELLS; DYSFUNCTION; NEURONS; DEATH Multiple languages Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13437