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Global Translational Medicine TEs link to Parkinson’s risk and progression

The exact cause of PD remains incompletely TEs have been recognized for their pivotal roles in
understood, with a growing body of evidence indicating shaping genome structure, function, and evolution .
[24]
that several factors, such as genetics, environmental Various mechanisms have evolved to suppress uncontrolled
factors, oxidative stress, and aging, contribute to an TE activity, such as epigenetic silencing mechanisms
increased risk of the disease . It is estimated that induced by DNA methylation . In the human genome,
[9]
[25]
approximately 15% of PD patients have a family history most TEs gradually lose their transposition ability due
[10]
of the disorder . Furthermore, research has identified to accumulated mutations during continuous evolution.
around 20 gene mutations associated with familial PD, Only LINE1, SINE-VNTR-Alus (SVA), and Alu elements
[13]
[11]
including genes SNCA , PRKN , and LRRK2 . The remain active . The earliest reports of TE insertion
[12]
[26]
interplay of genetic and environmental factors plays causing disease were related to hemophilia A, where LINE1
a significant role in the development of sporadic PD. insertions were discovered in the 14 exon of the F8 gene in
th
Large-scale genome-wide association studies (GWAS) two patients . Recent research has further substantiated
[27]
have identified several dozen risk variants that may the role of TE polymorphisms, demonstrating strong
exert cumulative effects with relatively low impacts . linkage disequilibrium (LD) with GWAS risk signals for
[14]
A recent GWAS analysis of PD identified 90 independent specific human diseases . Studies have demonstrated
[28]
autosomal risk signals. However, this analysis only that TE insertions primarily induce deleterious effects
explained 16–36% of heritability associated with PD, through three pathways. First, the integration of novel TEs
implying the existence of additional undiscovered into exonic regions can disrupt normal gene expression in
[15]
risk variants . To address this gap in knowledge, two the human genome. Second, RNA transcribed or proteins
potential approaches emerge: the first involves increasing translated from TEs may impact host physiological
the sample size, while the second entails incorporating activities. Finally, an increased frequency of ectopic
other types of variants into GWAS analysis. In a recent recombination between subfamilies of the same type of TE
GWAS study , short tandem repeats (STRs) were induces chromosomal rearrangement events [29,30] .
[16]
reported to be associated with the PD risk, resulting in an
increase in the heritability of PD estimate from 26.9% to Compared to the majority of ancient TEs that remain
28.8%. In addition, another study identified two common immobile within the human genome, non-reference TEs
X-chromosome variants linked to PD risk. These are relatively younger and more active. Some studies have
[17]
findings highlight the importance of exploring different suggested that these non-reference TEs exhibit activity
types of variants to gain a comprehensive understanding in the brain and may contribute to vulnerability to brain
[31]
of the genetic architecture underlying PD. disorders . In a recent investigation, several dozen SVA
insertion polymorphisms were reported to be linked
Transposable elements (TEs) are nucleotide sequences to PD progression using data from the Parkinson’s
[32]
widely present in the human genome, varying in length Progression Markers Initiative (PPMI) cohort. Similarly,
from 100 bp to 10 kb, and capable of independent another recent study, also utilizing PPMI cohort whole-
replication and movement . TEs account for nearly half of genome data, revealed a significant correlation between
[18]
the human genome and are categorized into two classes TE polymorphisms and the progression of PD . In this
[19]
[33]
according to their insertion mechanisms: retrotransposons study, we conducted a genome-wide analysis to explore the
(class 1) and DNA transposons (class 2) . The former is associations between non-reference TE polymorphisms
[20]
commonly referred to as the “copy-and-paste” mechanism, and the risk and progression of PD based on data from three
while the latter is known as the “cut-and-paste” independent cohorts. In addition, we integrated whole-
mechanism [18,21] . Retrotransposons consist of two subtypes: blood transcriptomic data and investigated the association
long terminal repeat (LTR) retrotransposons and non-long between TE polymorphisms and gene expression through
terminal repeat (non-LTR) retrotransposons, depending TE expression quantitative trait loci (TE-eQTL) analysis.
on the presence of LTR sequences at both sides. Non-
LTR retrotransposons include short interspersed nuclear 2. Materials and methods
elements (SINEs) and long interspersed nuclear elements
(LINEs) . TEs can be classified into two categories based 2.1. Study participants and quality control
[22]
on the ability to independently complete insertion events: The study’s subjects were sourced from the Parkinson’s
autonomous elements and non-autonomous elements. Progression Markers Initiative (PPMI, https://ppmi-info.
Autonomous TEs can encode the proteins required org) , the PD Biomarker Program (PDBP, https://pdbp.
[34]
for insertion events, while non-autonomous TEs rely ninds.nih.gov) , and the Fox Investigation for New
[35]
on proteins encoded by autonomous TEs to complete Discovery of Biomarkers (BioFIND, https://biofind.loni.
insertion events . usc.edu) . All data utilized were obtained with proper
[23]
[36]
Volume 2 Issue 3 (2023) 2 https://doi.org/10.36922/gtm.1583