JNNP: Serum peroxidase 3 is reduced in Parkinson's disease genetic carriers

Leucine-rich repeat kinase 2 (LRRK2) mutations have been associated with
autosomal dominant Parkinson's disease (PD).
G2019S remains the most common mutation but is rare in Asia, while Asian-specific variants of LRRK2 are associated
with an increased risk of PD.
LRRK1 interacts with human peroxidase progen 3 (PRDX3), a mitochondrial member of the thioredoxin (Trx) peroxidase antioxidant family, increasing its inhibitory effect and leading to mitochondrial dysfunction and oxidative damage
.
LRRK2 mutation reduces peroxidase activity and increases neuronal cell death
.
Serum PRDX3 is a surrogate marker of peroxidase activity, and lower levels reflect lower peroxidase activity, but peripheral PRDX3 levels
have not been studied in patients with PD with or without LRRK2 mutations.
This article assumes that PRDX3 levels can distinguish between PD LRRK2 mutation carriers (PD+LRRK2+) and LRRK non-mutant carriers (PD+RLRK2−).

This article was published in the Journal of Neurology, Neurosurgery & Psychiatry
.

Participants were recruited
from the National Institute of Neuroscience, Singapore from November 2014 to October 2019.
All patients with PD met the criteria of the National Institute of Neurological Disorders and Stroke for the diagnosis of
PD.
Functional status is determined by the Hoehn and Yahr scoring system, and the Movement Disorders Society Unified Parkinson's Disease Rating Scale (UPDRS) Part III exercise component measures exercise severity
.
Global cognition was measured using the Miniature Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) tool
.
The healthy control group (HC) was recruited from the community and had no significant neurological, psychiatric, or systemic illness
.
G2019S samples courtesy
of the Michael J.
Fox Foundation LRRK2 Cohort Consortium (LCC).
After dilution 150-fold, serum PRDX3
was determined by enzyme-linked immunosorbent assay (LS-F12395, LifeSpan BioSeciences, USA).
The precision within the analysis is 5.
6%.

A logarithmic transformation of the PRDX3 levels is performed to achieve a normal distribution
.
A univariate general linear model that controls age, sex, and course of disease, followed by post-hoc testing and Bonferroni correction
.
The correlation
between clinical variables and serum PRDX3 levels was analyzed using the Spearman correlation coefficient.

Demographic and clinical characteristics of all subjects, serum PRDX3 levels in the disease group

The demographics and clinical characteristics of both cohorts are shown
.
In the NNI cohort, age, sex, age of onset, course of disease, MMSE, MoCA, UPDRS motor score, and H&Y stage of PD+LRRK2
.
Patients are comparable
to PD+LRRK+ patients.
In the LLC cohort, the age, sex, and age of onset of patients with PD+LRRK2 were similar to those in patients with PD+LRRK+, but the course of disease was longer in patients with PD+LRK+ (p=0.
023).

In the NNI cohort, serum PRDX3 levels were significantly reduced in the PD+LRRK+ group and in the PD+LRR group (p<0.
001;) and HC (p=0.
002), controlling for age, sex, and course of
disease.
There was no significant difference in serum PRDX3 levels between patients with PD+LRRK and HC (p=0.
520).

Serum PRDX3 levels were not significantly correlated with age, sex, age of onset, and course of disease in each disease group, nor were they significantly correlated with clinical variables (MMSE, MoCA, H&Y, and exercise score) (p>0.
05).

In the LCC cohort, PRDX3 levels in G2019S+PD carriers were lower than PD-LRRK2- (p=0.
184;) and PD+LRRK2- (p=1.
0), a trend that was not significant
.
PRDX3 levels were significantly associated with disease course (rs=−0.
414, p=0.
017), PD+LRRK2+; PD+LRRK2 - age (rs=0.
474, p=0.
001) and age of onset (rs: 0.
396, p=0.
006).

Serum PRDX3 was significantly reduced in PD carriers of LRRK2 risk variants G2385R and R1628P compared with PD non-carriers and controls, and negatively correlated
with the course of disease between G2019S carriers and non-carriers.
These variant PD carriers have a faster
decline in exercise capacity compared to non-carriers.
We found a similar trend of lower PRDX3 levels between G2019S carriers and non-carriers, although a smaller sample size could explain why statistical significance was not achieved
.
Functionally, LRRK2 inactivates
PRDX3, the most important hydrogen peroxide H(2)O(2) scavenger in mitochondria.
In vitro, the loss of PRDX3 leads to increased intracellular hydrogen peroxide levels, mitochondrial damage, and apoptosis sensitivity
.
In vivo, overexpression of PRDX3 in transgenic mice (Tg (PRDX3) mice) in turn reduced hydrogen peroxide levels and increased resistance to stress-induced apoptosis
.

In summary, through two separate cohorts, we highlighted, for the first time, that LRRK2 PD risk variant/mutant carriers had reduced
serum PRDX3 (biologically relevant to LRRK1) levels in LRRK2 PD risk variants/mutant carriers compared to non-carrier patients and controls.
These findings provide impetus
for further research into PRDX3 as a possible biomarker for clinical progression.