Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia

Abstract

Peroxiredoxin 3 (PRDX3) belongs to a superfamily of peroxidases that function as protective antioxidant enzymes. Among the six isoforms (PRDX1–PRDX6), PRDX3 is the only protein exclusively localized to the mitochondria, which are the main source of reactive oxygen species. Excessive levels of reactive oxygen species are harmful to cells, inducing mitochondrial dysfunction, DNA damage, lipid and protein oxidation and ultimately apoptosis. Neuronal cell damage induced by oxidative stress has been associated with numerous neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. Leveraging the large aggregation of genomic ataxia datasets from the PREPARE (Preparing for Therapies in Autosomal Recessive Ataxias) network, we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration. The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration. Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity. Moreover, PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to apoptosis triggered by reactive oxygen species. Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress. Our findings reveal a central role for mitochondria and the implication of oxidative stress in PRDX3 disease pathogenesis and cerebellar vulnerability and suggest targets for future therapeutic approaches.

Microglia: The breakthrough to treat neovascularization and repair blood-retinal barrier in retinopathy

“…In the EAU mouse model, the addition of Icariin upregulates PRDX3 which transfers the microglia phenotype from pro-inflammatory to anti-inflammatory and alleviates the state of illness ( Wang et al, 2022 ). Thereinto, PRDX3 , a primary isoform of six peroxidases in mitochondria, swiftly scavenges abnormal accumulation of H2O2 to decrease apoptosis and damage caused by oxidative stress ( Rebelo et al, 2021 ).…”

Icariin alleviates uveitis by targeting peroxiredoxin 3 to modulate retinal microglia M1/M2 phenotypic polarization

“…As an important mitochondrial antioxidant protein, PRDX3 is the most plentiful and efficient H 2 O 2 eliminating enzyme in mitochondria, playing a major role against oxidative stress [ 9 ]. Being oxidized into inactive dimer form, PRDX3 scavenges H 2 O 2 and effectively prevents oxidative stress, apoptosis and cellular damage [ 10 ]. The increase of mitochondrial H 2 O 2 is a critical pathological process of EAU.…”

Common methods in mitochondrial research (Review)

“…Therefore, the rapid and accurate quantification of AP sites in mtDNA is crucial for the real-time assessment of mtdNA oxidative damage. Researchers have used a specific fluorescent probe (BTBM-CN2) for the real-time detection of mtdNA (375)(376)(377)(378). At ~20 sec after contact with AP sites, red fluorescence is detectable at 598 nm and after ~100 sec, green fluorescence is detectable at 480 nm.…”

“…More AP sites result in green fluorescence with greater intensity and duration and the degree of mtdNA damage can be quantified based on the time of appearance and intensity of fluorescence at 480 nm. doxorubicin (dox), a common anticancer drug, not only causes damage to the nuclear dNA of cells but can also be rapidly inserted into the mtdNA of living cells, causing the aggregation of mtdNA nucleoids and changing the distribution of nuclear proteins (375)(376)(377)(378)(379)(380)(381)(382). Therefore, after dox induces mtdNA damage, morphological changes of mtdNA can be tracked in real time using the two-photon fluorescent probe CNQ, which emits red fluorescence and is localized to mtdNA.…”