RORA PROTEIN MAY HELP EXPLAIN PARKINSON’S SEX-RELATED DIFFERENCES

A specific protein associated with sex hormone production may shed light on the sex-related differences in Parkinson’s observed between men and women, according to a recent study.

Levels of this protein, called retinoic acid receptor-related orphan receptor alpha (RORA), are higher in the blood of men with the neurodegenerative disease compared with healthy men, whereas women have similar levels regardless of whether they have Parkinson’s.

RORA is also found to be significantly higher in healthy women than in healthy men. In addition, a cell culture model of Parkinson’s shows activation of RORA is neuroprotective via a number of different mechanisms.

The findings overall support “a role for RORA in sex-specific aspects of [Parkinson’s],” researchers wrote. Moreover, the data highlight “the translational potential for RORA ligands [modulators].”

The study, “Neuroprotective role for RORA in Parkinson’s revealed by analysis of post-mortem brain and a dopaminergic cell line,” was published in npj Parkinson’s Disease.

Men more likely to develop Parkinson’s

There are a number of known sex differences in Parkinson’s risk and expression, with men being more likely to develop the neurodegenerative disease. Moreover, disease presentation and responses to treatment may differ markedly between the sexes.

The factors underlying these differences are not entirely known, but preclinical studies have suggested there could be a neuroprotective effect of circulating forms of estrogen in women.

Central aromatase is the enzyme responsible for the production of sex hormones, including estrogen, and central aromatase activity is regulated by RORA.

Evidence suggests that RORA can protect nerve cells against oxidative stress, a type of cellular damage in which there are too many toxic reactive oxygen species (ROS) molecules and a lack of antioxidant molecules to counterbalance them. Oxidative stress is implicated in the loss of dopamine-producing nerve cells that characterizes Parkinson’s.

In the study, scientists investigated whether RORA might be a factor underlying sex-related differences in Parkinson’s.

First, they examined activity of both the RORA gene and RORA, its protein product, in post-mortem brain tissue from 14 late-stage Parkinson’s patients and 11 age- and sex-matched control samples without Parkinson’s.

Specifically, they were looking in the substantia nigra pars compacta (SNpc), a key brain region where dopamine-producing cells are lost in the neurodegenerative disease.

Among healthy adults, RORA gene activity was significantly higher in women than in men.

The researchers also found a significant, twofold increase in RORA activity in samples from male patients relative to healthy men, whereas all the samples from women showed comparable levels of RORA activity.

Levels of the RORA protein closely followed this pattern, but the findings were not statistically significant.

The scientists proposed that higher levels of RORA in healthy women “offers resilience to neurodegenerative processes relative to men.” On the other hand, the increase observed in men with Parkinson’s could be “a neuroprotective adaptation to the disease whilst this may already be at its maximum capacity in females.”

Findings support ‘protective and sexually differentiating role for RORA’

To learn more, the researchers examined the effects of a RORA activator, or agonist, in a cell culture model of Parkinson’s.

In the model, a chemical called 6-OHDA causes significant toxicity to nerve cells, leading to their death. Cells exposed to the toxin were found to significantly increase their production of RORA.

Treatment with the RORA agonist significantly protected the cells against this cell death, whereas treatment with a RORA blocker, or antagonist, exacerbated their degeneration.

It appeared that these neuroprotective effects of RORA activation were mediated via different mechanisms related to reductions in markers of oxidative stress-induced cell death.

For example, the treatment significantly reduced levels of some enzymes belonging to the NOX family, which are major sources of ROS in neurodegenerative diseases.

Moreover, the agonist was associated with reduced ROS production in mitochondria, the cellular compartments responsible for energy production. Mitochondrial dysfunction and oxidative stress are closely linked and have been implicated in Parkinson’s.

“This is the first demonstration that there are inherent sex differences in RORA … in the human SNpc,” the researchers wrote.

“Collectively, they [the findings] support a protective and sexually differentiating role for RORA in [Parkinson’s] and highlight the translational importance of RORA,” the team concluded.