Premature ovarian ageing following heterozygous loss of Senataxin

Abstract

Premature loss of ovarian activity before 40 years of age is known as primary ovarian insufficiency (POI) and occurs in ∼1% of women. A more subtle decline in ovarian activity, known as premature ovarian ageing (POA), occurs in ∼10% of women. Despite the high prevalence of POA, very little is known regarding its genetic causation. Senataxin (SETX) is an RNA/DNA helicase involved in repair of oxidative stress-induced DNA damage. Homozygous mutation of SETX leads to the neurodegenerative disorder, ataxia oculomotor apraxia type 2 (AOA2). There have been reports of POI in AOA2 females suggesting a link between SETX and ovarian ageing. Here, we studied female mice lacking either one (Setx+/−) or both (Setx−/−) copies of SETX over a 12- to 14-month period. We find that DNA damage is increased in oocytes from 8-month-old Setx+/− and Setx−/− females compared with Setx+/+ oocytes leading to a marked reduction in all classes of ovarian follicles at least 4 months earlier than typically occurs in female mice. Furthermore, during a 12-month long mating trial, Setx+/− and Setx−/− females produced significantly fewer pups than Setx+/+ females from 7 months of age onwards. These data show that SETX is critical for preventing POA in mice, likely by preserving DNA integrity in oocytes. Intriguingly, heterozygous Setx loss causes an equally severe impact on ovarian ageing as homozygous Setx loss. Because heterozygous SETX disruption is less likely to produce systemic effects, SETX compromise could underpin some cases of insidious POA.

Senataxin: A New Guardian of the Female Germline Important for Delaying Ovarian Aging

“…We then studied aging female mice bearing in mind that female mice typically exhibit overt signs of reproductive aging from around 12 months of age when both oocyte numbers and developmental competence decline markedly ( Pan et al, 2008 ; Greaney et al, 2018 ; Iljas et al, 2020 ). Using the DSB marker, γH2AX, we found that by 8 months of age, there were low levels of damage in SETX +/+ ovaries as expected ( Subramanian et al, 2021 ). In contrast, follicle-enclosed oocytes within SETX −/− ovaries were already showing over 3-fold higher levels of damage.…”

“…In contrast, follicle-enclosed oocytes within SETX −/− ovaries were already showing over 3-fold higher levels of damage. Moreover, 8-month-old SETX −/− follicles showed similarly elevated levels of TUNEL staining ( Subramanian et al, 2021 ) altogether indicating that in the absence of Setx, oocytes within ovaries prematurely accumulated DNA damage that triggered apoptosis. Entirely in keeping with premature depletion of the ovarian reserve, 8-month-old SETX −/− ovaries contained less than half the numbers of all follicle stages seen in SETX +/+ ovaries and produced less than half the numbers of fully-grown oocytes following hormonal priming ( Subramanian et al, 2021 ).…”

“…Moreover, 8-month-old SETX −/− follicles showed similarly elevated levels of TUNEL staining ( Subramanian et al, 2021 ) altogether indicating that in the absence of Setx, oocytes within ovaries prematurely accumulated DNA damage that triggered apoptosis. Entirely in keeping with premature depletion of the ovarian reserve, 8-month-old SETX −/− ovaries contained less than half the numbers of all follicle stages seen in SETX +/+ ovaries and produced less than half the numbers of fully-grown oocytes following hormonal priming ( Subramanian et al, 2021 ). Collectively, therefore, these data show that in oocytes, Setx’s role is restricted to aging and prevents early-onset accumulation of DNA damage that would otherwise induce premature depletion of the ovarian reserve.…”

“…At 4 months of age, isolated fully-grown SETX +/+ and SETX −/− oocytes had low levels of DNA damage ( Subramanian et al, 2020 , 2021 ). This remained largely unchanged at 8 months of age for SETX +/+ oocytes contrasting sharply with a 3–4-fold higher increase in SETX −/− oocytes consistent with the increased damage observed at this age in growing follicle-enclosed SETX −/− oocytes.…”

“…Separate from its role in neurological disorders, more recent research has begun to shed light on a lesser-known role of Setx in reproduction ( Becherel et al, 2013 , 2019 ; Subramanian et al, 2020 , 2021 ). Setx has been shown to be critical for male fertility through maintaining genomic integrity during spermatogenesis ( Becherel et al, 2013 ).…”