Dataset Information

UQCRC1 variants in early-onset and familial Parkinson's disease in a Taiwanese cohort.

ABSTRACT:

Background

A recent Taiwanese study reported variants of the ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene linked to autosomal dominant parkinsonism with polyneuropathy. This study investigated the pathogenicity of UQCRC1 in a Taiwanese cohort of patients with Parkinson's disease (PD).

Method

This study involved 107 participants (98 with early-onset PD and nine with familial PD). All UQCRC1 coding exons and exon-intron boundaries were sequenced. The rarity and pathogenicity of the identified variants were analyzed. The carrier frequencies of our cohort and the Taiwan Biobank were compared through a Pearson's χ² or Fisher's exact test along with Bonferroni corrections.

Results

Three missense variants (c.643G > C, p.D215H; c.800C > G, p.P267R, and c.923A > G, p.N308S) and seven rare variants were identified. No significant differences in the missense-variant carrier frequency were noted between our cohort and individuals in the Taiwan Biobank. Furthermore, no significant associations were noted between the variants and the risk of PD.

Conclusions

Our study is not supporting a role of UQCRC1 variants in PD.

SUBMITTER: Liao TW

PROVIDER: S-EPMC9780373 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

<i>UQCRC1</i> variants in early-onset and familial Parkinson's disease in a Taiwanese cohort.

Liao Ting-Wei TW Chao Chih-Ying CY Wu Yih-Ru YR

Frontiers in neurology 20221209

<h4>Background</h4>A recent Taiwanese study reported variants of the ubiquinol-cytochrome c reductase core protein 1 (<i>UQCRC1</i>) gene linked to autosomal dominant parkinsonism with polyneuropathy. This study investigated the pathogenicity of <i>UQCRC1</i> in a Taiwanese cohort of patients with Parkinson's disease (PD).<h4>Method</h4>This study involved 107 participants (98 with early-onset PD and nine with familial PD). All <i>UQCRC1</i> coding exons and exon-intron boundaries were sequenced ...[more]

PMID: 36570444

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Project description:Parkinson's Disease (PD) is characterized by the accumulation of Lewy bodies in dopaminergic neurons. The main protein component of Lewy bodies, α-synuclein (αS), is also firmly linked to PD through the identification of a number of single point mutations that are autosomal dominant for early-onset disease. Consequently, the misfolding and subsequent aggregation of αS is thought to be a key stage in the development and progression of PD. Therefore, modulating the aggregation pathway of αS is an attractive therapeutic target. Owing to the fact that all but one of the familial mutations is located in the preNAC 45-54 region of αS, we previously designed a semi-rational library using this sequence as a design scaffold. The 45-54 peptide library was screened using a protein-fragment complementation assay approach, leading to the identification of the 4554W peptide. The peptide was subsequently found to be effective in inhibiting primary nucleation of αS, the earliest stage of the aggregation pathway. Here, we build upon this previous work by screening the same 45-54 library against five of the known αS single-point mutants that are associated with early-onset PD (A30P, E46K, H50Q, G51D, and A53T). These point mutations lead to a rapid acceleration of PD pathology by altering either the rate or type of aggregates formed. All ultimately lead to earlier disease onset and were therefore used to enforce increased assay stringency during the library screening process. The ultimate aim was to identify a peptide that is effective against not only the familial αS variant from which it has been selected but that is also effective against WT αS. Screening resulted in five peptides that shared common residues at some positions, while deviating at others. All reduced aggregation of the respective target, with several also identified to be effective at reducing aggregation when incubated with other variants. In addition, our results demonstrate that a previously optimized peptide, 4554W(N6A), is highly effective against not only WT αS but also several of the single-point mutant forms and hence is a suitable baseline for further work toward a PD therapeutic.