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Dysfunctional Alternative Polyadenylation Modifies the Penetrance of LRRK2 Variants in Parkinson's Disease

Songyu Yang1,2, Yixiao Zhu1,2, Pei Yu1

  • 1National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.

Movement Disorders : Official Journal of the Movement Disorder Society
|November 15, 2025
PubMed
Abstract

Insights

Dysfunctional alternative polyadenylation (APA) influences Parkinson's disease (PD) onset in LRRK2 variant carriers. This molecular mechanism helps explain variable PD penetrance and symptom severity in genetic Parkinson's disease.

Area of Science:

  • Genetics and Molecular Biology
  • Neuroscience
  • Biochemistry

Background:

  • Pathogenic variants in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are a leading genetic cause of Parkinson's disease (PD).
  • Incomplete penetrance of LRRK2 variants leads to varied PD onset, with underlying molecular modifiers poorly understood.
  • Alternative polyadenylation (APA) is a critical post-transcriptional regulatory process.

Purpose of the Study:

  • To investigate if dysfunctional APA modulates the penetrance of LRRK2 variants in Parkinson's disease.
  • To identify APA events associated with LRRK2 variants and their role in PD.
  • To explore the link between dysfunctional APA, immune cell composition, and PD symptom severity.

Main Methods:

  • RNA sequencing data from 905 participants in the Parkinson's Progression Markers Initiative (PPMI) were analyzed.
  • Dysfunctional APA was quantified using the percentage of distal polyadenylation site usage index (PDUI).
  • Association of APA with LRRK2 variants, PD status, symptom severity, and immune cell composition was evaluated, including a sensitivity analysis for the G2019S variant.

Main Results:

  • PD patients showed over double the number of dysfunctional APA events linked to LRRK2 variants compared to healthy controls.
  • PD-specific APA events implicated immune disorders, amyloid fiber formation, and proteases, all relevant to PD pathogenesis.
  • Fourteen dysfunctional APA events differentiated symptomatic from asymptomatic LRRK2 carriers, correlating with immune cell profiles and PD symptom severity. The G2019S variant largely mirrored these findings.

Conclusions:

  • Dysfunctional APA emerges as a significant modifier of LRRK2 variant penetrance in Parkinson's disease.
  • These APA alterations contribute to the onset and variability of PD in LRRK2 variant carriers.
  • The findings highlight APA as a potential therapeutic target for LRRK2-associated Parkinson's disease.
Keywords:
LRRK2 variantsParkinson's diseaseRNA‐seqalternative polyadenylationincomplete penetrance

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