Rapid motor progression of Parkinson’s disease associates with clinical and genetic variants

Cao, Ling-Xiao; Jiang, Yong; Piao, Ying-shan; Huang, Yue

doi:10.52586/5044

Cited by 8 publications

(6 citation statements)

References 45 publications

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“…While rs591323 is also an intron variant, the extent to which its variation impacts the activity of FGF20 remains to be investigated ( 63 ). In our previous study, IP6K2 rs12497850 also displayed a potential association with motor progression, yet it did not meet the threshold for significance after multiple comparison correction ( 17 ). IP6K2 has been shown to participate in the process of cell death and apoptosis.…”

Section: Discussionmentioning

confidence: 94%

“…Genetic factors have been shown to contribute to the rapidity of motor deterioration in PD (17)(18)(19)(20), but the extent of genetic contribution to the cognitive decline in PD is poorly understood, partially due to the lack of a stable cognitive assessment tool for PD. Since the application of genome-wide association studies (GWAS) in PD, more than 90 independent single nucleotide polymorphisms (SNPs) have been identified in association with PD (21,22), implicating multiple molecular pathways involved in the process of disease initiation.…”

Section: Introductionmentioning

confidence: 99%

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Assessment tools for cognitive performance in Parkinson’s disease and its genetic contributors

Cao,

Kong,

Chan

et al. 2024

Front. Neurol.

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BackgroundWe have shown that genetic factors associating with motor progression of Parkinson’s disease (PD), but their roles in cognitive function is poorly understood. One reason is that while cognitive performance in PD can be evaluated by various cognitive scales, there is no definitive guide indicating which tool performs better.MethodsData were obtained from the Parkinson’s Progression Markers Initiative, where cognitive performance was assessed using five cognitive screening tools, including Symbol Digit Modalities Test (SDMT), Montreal Cognitive Assessment, Benton Judgment of Line Orientation, Modified Semantic Fluency Test, and Letter Number Sequencing Test, at baseline and subsequent annual follow-up visit for 5 years. Genetic data including ApoE and other PD risk genetic information were also obtained. We used SPSS-receiver operating characteristic and ANOVA repeated measures to evaluate which cognitive assessment is the best reflecting cognitive performance in PD at early stage and over time. Logistic regression analyses were used to determine the genetic associations with the rapidity of cognitive decline in PD.ResultsSDMT performed better in detecting mild cognitive impairment at baseline (AUC = 0.763), and SDMT was the only tool showing a steady cognitive decline during longitudinal observation. Multigenetic factors significantly associated with cognitive impairment at early stage of the disease (AUC = 0.950) with IP6K2 rs12497850 more evident, and a significantly faster decline (AUC = 0.831) within 5 years after motor onset, particularly in those carrying FGF20 rs591323.ConclusionSDMT is a preferable cognitive assessment tool for PD and genetic factors synergistically contribute to the cognitive dysfunction in PD.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Assessment tools for cognitive performance in Parkinson’s disease and its genetic contributors

Cao,

Kong,

Chan

et al. 2024

Front. Neurol.

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“…It has been reported that the TMEM175 M393T mutation affects the progression of PD. Through studying a cohort of 341 longitudinally followed PD patients, the M393T mutation was found to be associated with the rate of cognitive decline [28] and the rate of motor decline in PD, with p.M393T carriers declining more rapidly than patients without this mutation [28,98]. Moreover, multiple GWASs and meta-analysis of age at onset of PD have identified the TMEM175 rs34311866 (p.M393T) as a genomewide significant variant that is associated with earlier age at onset of PD [72,92,99,100].…”

Section: Two Important Snps Of Tmem175 In Parkinson's Diseasementioning

confidence: 99%

Transmembrane Protein 175, a Lysosomal Ion Channel Related to Parkinson’s Disease

2023

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Lysosomes are membrane-bound organelles with an acidic lumen and are traditionally characterized as a recycling center in cells. Lysosomal ion channels are integral membrane proteins that form pores in lysosomal membranes and allow the influx and efflux of essential ions. Transmembrane protein 175 (TMEM175) is a unique lysosomal potassium channel that shares little sequence similarity with other potassium channels. It is found in bacteria, archaea, and animals. The prokaryotic TMEM175 consists of one six-transmembrane domain that adopts a tetrameric architecture, while the mammalian TMEM175 is comprised of two six-transmembrane domains that function as a dimer in lysosomal membranes. Previous studies have demonstrated that the lysosomal K+ conductance mediated by TMEM175 is critical for setting membrane potential, maintaining pH stability, and regulating lysosome–autophagosome fusion. AKT and B-cell lymphoma 2 regulate TMEM175’s channel activity through direct binding. Two recent studies reported that the human TMEM175 is also a proton-selective channel under normal lysosomal pH (4.5–5.5) as the K+ permeation dramatically decreased at low pH while the H+ current through TMEM175 greatly increased. Genome-wide association studies and functional studies in mouse models have established that TMEM175 is implicated in the pathogenesis of Parkinson’s disease, which sparks more research interests in this lysosomal channel.

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“…In the Asian cohort, SC2C, WBSCR17 , and BST1 showed a robust association with PD ( 15 , 18 ). Intriguingly, the fact that familial PD genes have been identified by GWAS means that familial PD genes are involved in the pathogenesis of sporadic PD, strongly suggesting common pathogenic pathways between familial and sporadic PD, or that multiple concurrent variants of familial PD genes may relate to the rapid motor progression of sporadic PD ( 35 ).…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

Clinical Manifestations and Molecular Backgrounds of Parkinson's Disease Regarding Genes Identified From Familial and Population Studies

et al. 2022

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Over the past 20 years, numerous robust analyses have identified over 20 genes related to familial Parkinson's disease (PD), thereby uncovering its molecular underpinnings and giving rise to more sophisticated approaches to investigate its pathogenesis. α-Synuclein is a major component of Lewy bodies (LBs) and behaves in a prion-like manner. The discovery of α-Synuclein enables an in-depth understanding of the pathology behind the generation of LBs and dopaminergic neuronal loss. Understanding the pathophysiological roles of genes identified from PD families is uncovering the molecular mechanisms, such as defects in dopamine biosynthesis and metabolism, excessive oxidative stress, dysfunction of mitochondrial maintenance, and abnormalities in the autophagy–lysosome pathway, involved in PD pathogenesis. This review summarizes the current knowledge on familial PD genes detected by both single-gene analyses obeying the Mendelian inheritance and meta-analyses of genome-wide association studies (GWAS) from genome libraries of PD. Studying the functional role of these genes might potentially elucidate the pathological mechanisms underlying familial PD and sporadic PD and stimulate future investigations to decipher the common pathways between the diseases.

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Rapid motor progression of Parkinson’s disease associates with clinical and genetic variants

Cited by 8 publications

References 45 publications

Assessment tools for cognitive performance in Parkinson’s disease and its genetic contributors

Assessment tools for cognitive performance in Parkinson’s disease and its genetic contributors

Transmembrane Protein 175, a Lysosomal Ion Channel Related to Parkinson’s Disease

Clinical Manifestations and Molecular Backgrounds of Parkinson's Disease Regarding Genes Identified From Familial and Population Studies

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