Browsing by Author "Siddique, Teepu"

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    Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia
    (Oxford University Press, 2024) Thumbadoo, Kyrah M.; Dieriks, Birger V.; Murray, Helen C.; Swanson, Molly E. V.; Yoo, Ji Hun; Mehrabi, Nasim F.; Turner, Clinton; Dragunow, Michael; Faull, Richard L. M.; Curtis, Maurice A.; Siddique, Teepu; Shaw, Christopher E.; Newell, Kathy L.; Henden, Lyndal; Williams, Kelly L.; Nicholson, Garth A.; Scotter, Emma L.; Pathology and Laboratory Medicine, School of Medicine
    Pathogenic variants in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterized by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial amyotrophic lateral sclerosis and/or frontotemporal dementia cases not caused by UBQLN2 pathogenic variants, particularly C9orf72-linked cases. This makes the mechanistic role of mutant ubiquilin 2 protein and the value of ubiquilin 2 pathology for predicting genotype unclear. Here we examine a cohort of 44 genotypically diverse amyotrophic lateral sclerosis cases with or without frontotemporal dementia, including eight cases with UBQLN2 variants [resulting in p.S222G, p.P497H, p.P506S, p.T487I (two cases) and p.P497L (three cases)]. Using multiplexed (five-label) fluorescent immunohistochemistry, we mapped the co-localization of ubiquilin 2 with phosphorylated TDP-43, dipeptide repeat aggregates and p62 in the hippocampus of controls (n = 6), or amyotrophic lateral sclerosis with or without frontotemporal dementia in sporadic (n = 20), unknown familial (n = 3), SOD1-linked (n = 1), FUS-linked (n = 1), C9orf72-linked (n = 5) and UBQLN2-linked (n = 8) cases. We differentiate between (i) ubiquilin 2 aggregation together with phosphorylated TDP-43 or dipeptide repeat proteins; and (ii) ubiquilin 2 self-aggregation promoted by UBQLN2 pathogenic variants that cause amyotrophic lateral sclerosis and/or frontotemporal dementia. Overall, we describe a hippocampal protein aggregation signature that fully distinguishes mutant from wild-type ubiquilin 2 in amyotrophic lateral sclerosis with or without frontotemporal dementia, whereby mutant ubiquilin 2 is more prone than wild-type to aggregate independently of driving factors. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2-linked disease.
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    Identification of TMEM230 mutations in familial Parkinson's disease
    (Nature Research, 2016-07) Deng, Han-Xiang; Shi, Yong; Yang, Yi; Ahmeti, Kreshnik B.; Miller, Nimrod; Huang, Cao; Cheng, Lijun; Zhai, Hong; Deng, Sheng; Nuytemans, Karen; Corbett, Nicola J.; Kim, Myung Jong; Deng, Hao; Tang, Baisha; Yang, Ziquang; Xu, Yanming; Chen, Piao; Huang, Bo; Gao, Xiao-Ping; Song, Zhi; Liu, Zhenhua; Fecto, Faisal; Siddique, Nailah; Foroud, Tatiana; Jankovic, Joseph; Ghetti, Bernardino; Nicholson, Daniel A.; Krainc, Dimitri; Melen, Onur; Vance, Jeffery M.; Pericak-Vance, Margaret A.; Ma, Yong-Chao; Rajput, Ali H.; Siddique, Teepu; Medical and Molecular Genetics, School of Medicine
    Parkinson's disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms have led to the identification of mutations in several genes, which are linked to typical Parkinson's disease or parkinsonian disorders. The pathogenesis of Parkinson's disease remains largely elusive. Here we report a locus for autosomal dominant, clinically typical and Lewy body-confirmed Parkinson's disease on the short arm of chromosome 20 (20pter-p12) and identify TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinson's disease, with implications for understanding the pathogenic mechanism of Parkinson's disease and for developing rational therapies.
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    Whole-genome bisulfite sequencing of cell-free DNA unveils age-dependent and ALS-associated methylation alterations
    (Springer Nature, 2025-02-20) Jin, Yulin; Conneely, Karen N.; Ma, Wenjing; Naviaux, Robert K.; Siddique, Teepu; Allen, Emily G.; Guingrich, Sandra; Pascuzzi, Robert M.; Jin, Peng; Neurology, School of Medicine
    Background: Cell-free DNA (cfDNA) in plasma carries epigenetic signatures specific to tissue or cell of origin. Aberrant methylation patterns in circulating cfDNA have emerged as valuable tools for noninvasive cancer detection, prenatal diagnostics, and organ transplant assessment. Such epigenetic changes also hold significant promise for the diagnosis of neurodegenerative diseases, which often progresses slowly and has a lengthy asymptomatic period. However, genome-wide cfDNA methylation changes in neurodegenerative diseases remain poorly understood. Results: We used whole-genome bisulfite sequencing (WGBS) to profile age-dependent and ALS-associated methylation signatures in cfDNA from 30 individuals, including young and middle-aged controls, as well as ALS patients with matched controls. We identified 5,223 age-related differentially methylated loci (DMLs) (FDR < 0.05), with 51.6% showing hypomethylation in older individuals. Our results significantly overlapped with age-associated CpGs identified in a large blood-based epigenome-wide association study (EWAS). Comparing ALS patients to controls, we detected 1,045 differentially methylated regions (DMRs) in gene bodies, promoters, and intergenic regions. Notably, these DMRs were linked to key ALS-associated pathways, including endocytosis and cell adhesion. Integration with spinal cord transcriptomics revealed that 31% of DMR-associated genes exhibited differential expression in ALS patients compared to controls, with over 20 genes significantly correlating with disease duration. Furthermore, comparison with published single-nucleus RNA sequencing (snRNA-Seq) data of ALS demonstrated that cfDNA methylation changes reflects cell-type-specific gene dysregulation in the brain of ALS patients, particularly in excitatory neurons and astrocytes. Deconvolution of cfDNA methylation profiles suggested altered proportions of immune and liver-derived cfDNA in ALS patients. Conclusions: cfDNA methylation is a powerful tool for assessing age-related changes and ALS-specific molecular dysregulation by revealing perturbed locus, genes, and the proportional contributions of different tissues/cells to the plasma. This technique holds promise for clinical application in biomarker discovery across a broad spectrum of neurodegenerative disorders.