Astrocyte-specific deletion of the mitochondrial m-AAA protease reveals glial contribution to neurodegeneration

Autor: Simon Hess, Elena I. Rugarli, Susanne Brodesser, Désirée Schatton, Steffen Hermans, Peter Kloppenburg, Esther Barth, Thomas Langer, Eva R. Almajan, Sara Murru
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
Bergmann glia
Mitochondrial disease
Excitotoxicity
necroptosis
Mice
Transgenic
Biology
medicine.disease_cause
neuroinflammation
03 medical and health sciences
Cellular and Molecular Neuroscience
Purkinje Cells
0302 clinical medicine
spinocerebellar ataxia
Glutamate homeostasis
ATP-Dependent Proteases
Cerebellum
medicine
Animals
Neuroinflammation
Research Articles
Inflammation
Neurodegeneration
Glutamate receptor
Metalloendopeptidases
Neurodegenerative Diseases
medicine.disease
Purkinje neuron
Cell biology
Mitochondria
Disease Models
Animal
mitochondrial disease
030104 developmental biology
medicine.anatomical_structure
Neurology
Astrocytes
Spinocerebellar ataxia
ATPases Associated with Diverse Cellular Activities
Female
glutamate transporter
030217 neurology & neurosurgery
Astrocyte
Research Article
Zdroj: Glia
ISSN: 1098-1136
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: