paper 3

Citation Information

  • Vacchiano, V.; Bartoletti-Stella, A.; Rizzo, G.; Avoni, P.; Parchi, P.; Salvi, F.; Liguori, R.; Capellari, S.

  • Title: Frequency of Parkinson’s Disease Genes and Role of PARK2 in Amyotrophic Lateral Sclerosis: An NGS Study

  • Journal: Genes

  • Year: 2022

  • Volume: 13

  • Article: 1306

  • DOI: https://doi.org/10.3390/genes13081306

  • Academic Editor: Christopher Grunseich

  • Received: 27 May 2022

  • Accepted: 23 June 2022

  • Published: 22 July 2022

  • License: Creative Commons Attribution (CC BY)

Abstract

  • Amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) patients show a higher prevalence of Lewy body disease than the general population.

  • Around 30% of ALS patients also exhibit parkinsonian features.

  • Objective: To explore the frequency of Parkinson’s disease (PD)-causative genes in ALS patients compared to AD and healthy controls (HCs).

  • Methods: Next-generation sequencing (NGS) was performed on multigene panels, analyzing the following genes:

    • SNCA

    • LRRK2

    • PINK1

    • PARK2

    • PARK7

    • SYNJ1

    • CHCHD2

    • PLA2G6

    • GCH1

    • ATP13A2

    • DNAJC6

    • FBXO7

  • Additionally, the GBA gene, a PD risk factor, was analyzed.

  • Cohorts analyzed:

    • 130 ALS patients

    • 100 AD patients

    • 1686 healthy controls.

  • Results:

    • PD-related genes altered in 26.2% of ALS, 20% of AD patients, and 19.2% of HCs.

    • Autosomal recessive genes significantly more involved in ALS compared to AD and HCs (p = 0.021).

    • PARK2 variants more frequent in ALS than in AD and HCs, specifically the p.Arg402Cys variant increased in ALS (p = 0.025).

  • Conclusion: The study suggests a potential role of PD-related genes as risk modifiers in ALS pathogenesis.

1. Introduction

  • ALS is characterized by degeneration of both upper and lower motor neurons and is traditionally seen as a motor disease.

  • Up to 50% of ALS cases exhibit extra-motor features, including cognitive decline leading to frontotemporal dementia (FTD) in 10–15% of cases.

  • Epidemiological studies indicate higher ALS risk in offspring of PD patients and up to 30% of ALS patients display parkinsonian features.

  • A genetic link between ALS and PD has been established through GWAS, highlighting shared genetic risks across neurodegenerative diseases.

  • The C9Orf72 gene is prominent in ALS, showing manifestations of parkinsonism.

  • Other related disorders, such as multisystemic proteinopathy, present overlapping clinical features.

  • In Alzheimer’s patients, 50–60% with certain genetic mutations exhibit widespread α-synuclein pathology.

  • Around 5-10% of PD cases are classified as monogenic disorders, while mutations in genes like SNCA and LRRK2 lead to different PD forms.

2. Materials and Methods

  • Targeted Genes: Included known PD-causing genes (SNCA, LRRK2, PINK1, PARK2, PARK7, SYNJ1, CHCHD2, PLA2G6, GCH1, ATP13A2, DNAJC6, FBXO7) and the GBA gene.

  • Sample Collection: Genomic DNA isolated from peripheral blood via Maxwell 16 extractor (Promega).

  • Sequencing Process:

    • Performed using Illumina panels (either amplicon-based or probe-based).

    • Sequenced with MiSeq or NextSeq 500, using Illumina V2 kits, following 2 × 150 bp paired-end read cycles.

  • Data Analysis: Utilized in-house bioinformatics and variant filtration methodologies, including GATK v4 guidelines.

  • Variant Classification: Followed ACMG guidelines for interpretation of sequence variants, considering pathogenicity and significance.

  • Study Approval: Conducted under the Declaration of Helsinki, approved by local ethics committee.

3. Results

  • Analyzed 130 ALS and 100 AD patients. The findings are summarized as follows:

    • 19 ALS patients (14.6%) carried causative mutations in major ALS genes; no AD patients had pathogenic variants.

    • PD-related gene variants detected include:

    • LRRK2: 2 ALS (1.5%), 2 AD (2%), 62 HCs (3.7%)

    • PARK2: 8 ALS (6.2%), 4 AD (4%), 70 HCs (4.2%)

  • Overall detection rates summarized:

    • 31 ALS patients (23.8%) and 17 AD patients (17%) had at least one variant in a PD-related gene.

    • Conclusion drawn from statistical analyses indicates a significant presence of autosomal recessive PD-related variants in ALS compared to AD/HCs (p = 0.021).

  • PARK2 Variants: Recurrently identified in 6 ALS patients; p.Arg402Cys classified as VUS, enriched in ALS cohort (p = 0.025).

4. Discussion

  • The study indicates an increased presence of PD-related gene variants, particularly in autosomal recessive genes, as associated with ALS pathogenesis.

  • The lack of significant differences in clinical features points toward the possibility of these variants acting as risk modifiers rather than direct contributors.

  • Absence of SNCA variants in both ALS and AD cohorts aligns with past findings.

  • Presence of LRRK2 variants remains inconclusive regarding its direct role in ALS.

  • Genetic mutations in PARK2 and PINK1, linked with early-onset parkinsonism, imply their pathogenic potential in ALS as well.

  • GBA Gene: Variants were similarly observed across ALS and AD, reaffirming the need for further exploration of their significance in cognitive decline.

Study Implications & Limitations

  • The study highlights the importance of expanding genetic analyses in neurodegenerative diseases, particularly those overlapping with Lewy body disease.

  • Limitations include the sample size and lack of detailed neuropsychological assessments to correlate genetic findings with cognitive profiles.

  • Results warrant further investigation into the implications of identified variants in terms of ALS's heterogeneous phenotypes.