Abstract
Several neurodegenerative disorders exhibit selective vulnerability, with subsets of neurons more affected than others, possibly because of the high expression of an altered gene or the presence of particular features that make them more susceptible to insults. On the other hand, resilient neurons may display the ability to develop antioxidant defenses, particularly in diseases of mitochondrial origin, where oxidative stress might contribute to the neurodegenerative process. In this work, we investigated the oxidative stress response of embryonic fibroblasts and cortical neurons obtained from Afg3l2-KO mice. AFG3L2 encodes a subunit of a protease complex that is expressed in mitochondria and acts as both quality control and regulatory enzyme affecting respiration and mitochondrial dynamics. When cells were subjected to an acute oxidative stress protocol, the survival of AFG3L2-KO MEFs was not significantly influenced and was comparable to that of WT; however, the basal level of the antioxidant molecule glutathione was higher. Indeed, glutathione depletion strongly affected the viability of KO, but not of WT MEF, thereby indicating that oxidative stress is more elevated in KO MEF even though well controlled by glutathione. On the other hand, when cortical KO neurons were put in culture, they immediately appeared more vulnerable than WT to the acute oxidative stress condition, but after few days in vitro, the situation was reversed with KO neurons being more resistant than WT to acute stress. This compensatory, protective competence was not due to the upregulation of glutathione, rather of two mitochondrial antioxidant proteins: superoxide dismutase 2 and, at an even higher level, peroxiredoxin 3. This body of evidence sheds light on the capability of neurons to activate neuroprotective pathways and points the attention to peroxiredoxin 3, an antioxidant enzyme that might be critical for neuronal survival also in other disorders affecting mitochondria.
Highlights
AFG3L2 (ATPase family gene 3-like 2) encodes a subunit of the large m-AAA (ATPases associated with various cellular activities) protease complex expressed on the inner membrane of mitochondria and active on the matrix side
Since the defective expression of Afg3l2 was reported to promote oxidative stress in Purkinje cells [18] and to recapitulate the typical spinocerebellar ataxia type 28 (SCA28) mitochondrial dysfunctions in murine embryonic fibroblasts (MEFs) [4], we investigated the susceptibility of MEF cells obtained from Afg3l2-KO mice (KO MEFs) to oxidative conditions
Several neurodegenerative disorders are characterized by a selective neuronal vulnerability, meaning that subpopulations of neurons are more prone to death in response to a common pathological condition [32]
Summary
AFG3L2 (ATPase family gene 3-like 2) encodes a subunit of the large m-AAA (ATPases associated with various cellular activities) protease complex expressed on the inner membrane of mitochondria and active on the matrix side. A homozygous missense mutation in AFG3L2 causes the spastic ataxia type 5 (SPAX5), a different and more severe disease, characterized by earlyonset spasticity, myoclonic epilepsy, cerebellar atrophy, oculomotor apraxia, and dystonia [11]. The Afg3l2 haploinsufficiency in SCA28 causes several mitochondrial dysfunctions that include reduced assembly of respiratory complexes, swollen appearance, fragmentation and altered dendritic distribution, increase in oxidative stress, and calcium dysregulation [15, 16]. Haploinsufficiency does not mimic the genetic background of patients, it should be considered that the mutations in the proteolytic domain of Afg3l2, while not altering the protein levels, still reduce the overall activity of the complex of about 50%, providing a functional haploinsufficiency [5]. The heterozygous models functionally recapitulate the genetic settings of SCA28 patients and are currently used to study the molecular alterations in this disease
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