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

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.

Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

“…The reduced levels of GLAST, both due to a decreased total number of BG and to a reduced expression on the spared cells, in turn, translated in glutamate-mediated neurotoxicity on PCs that could be rescued by MAXER overexpression [46]. Reduced numbers of BG, due to their massive death, were also very recently described in a SCA28 mouse model, in which the mutated gene AFG3L2 was selectively expressed in astrocytes [72]. Here, BG death was only the endpoint of a progressive degenerative process, characterized by their ectopic position, aberrant morphology, decreased expression of the calcium-binding protein S100 and the glutamate transporter GLT-1, upregulation of GFAP, abnormal mitochondrial network, and activated metabolic stress response.…”

“…Cerebellar astrogliosis is not only among the first cell-intrinsic effects of the expression of ataxia-related genes in cerebellar astrocytes [58,72,73] but it is also probably one of the astrocytes' earliest responses to the abnormal behaviors of mutant neurons. Early astrocyte activation was indeed observed in both the cerebellar nuclei (CN) and cortex in a SCA21 mouse model in which the mutated gene TMEM240 was expressed only in neurons [74].…”

“…Indeed, the ablation in mice of the SLC1A3 gene, coding for the GLAST transporter, results in severe motor impairments and several missense mutations, either inherited or de novo, in the GLAST gene were shown to cause distinct forms of episodic ataxia (EA), whose symptoms severity appeared sometimes correlated with the extent of glutamate transporter dysfunction (Table 2) [88][89][90][91][92][93]. Moreover, reduced expressions of GLAST and/or GLT-1 were reported in models of SCA1, SCA7, and SCA28 in which the mutant genes were selectively expressed in astrocytes [46,56,72], indicating that the genetic alterations underlying some forms of ataxia may directly interfere with the astrocytes-mediated glutamate uptake.…”

Hedgehog Signaling Modulates Glial Proteostasis and Lifespan

“…This also induces a non-cell-autonomous response in neurons and results in loss of neurons in the lamina and loss of GluRIIB neurons in the adult brain (Wang et al, 2011). Moreover, astrocyte-specific depletion of the mitochondrial protease in mice (mAAA)-a protein involved in the protein quality control in mitochondriacauses neurological defects (motor impairment), neurodegeneration of Purkinje cells in the cerebellum, as well as a decline in synaptic function (Murru et al, 2019). All this suggests that glial proteostasis defects will hinder the supporting roles of glia in the nervous system (and therefore can have a direct consequence on neuronal viability), and chaperones expressed in glia may confer neuroprotection.…”

In situcharacterization of calcium fluxes in astrocytic mitochondria from the mouse striatum and hippocampus

“…This suggests that mitochondrial Ca 2+ fluxes in astrocytes are not 6 only critical for normal brain function, but can also significantly influence neurodegenerative processes. The central role played by astrocytic mitochondria during neurodegeneration is further highlighted by independent studies showing that disruption of astrocytic mitochondria exacerbates neurodegeneration in cerebellar Purkinje neurons 24 , attenuates neuroprotection following ischemia 25 , and even slows the recovery of mice from anesthesia 26 . Despite the many important roles ascribed to astrocytic mitochondria, and specifically to mitochondrial Ca 2+ fluxes in astrocytes during health and disease, we know very little with regard to the subcellular characteristics of astrocytic mitochondria in situ, whether or not Ca 2+ spontaneously fluxes into the mitochondria of astrocytes, and the extent to which astrocytic mitochondrial Ca 2+ events respond to neurotransmitter agonists.…”