A5086883137- Parkinson's Disease Mechanisms and Treatments
- Cellular transport and secretion
- Neurological disorders and treatments
- RNA regulation and disease
- Lysosomal Storage Disorders Research
- Genetics and Neurodevelopmental Disorders
- Genetic Neurodegenerative Diseases
- Metabolism and Genetic Disorders
- RNA modifications and cancer
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Neurological diseases and metabolism
- Amino Acid Enzymes and Metabolism
- Nuclear Receptors and Signaling
- Banana Cultivation and Research
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- Caveolin-1 and cellular processes
- Migraine and Headache Studies
- Neuroscience and Neuropharmacology Research
- Extracellular vesicles in disease
- Nicotinic Acetylcholine Receptors Study
- DNA Repair Mechanisms
- Neuroscience of respiration and sleep
- Nuclear Structure and Function
University of Florida
2021-2025
University of British Columbia
2017-2024
The University of Queensland
2013-2020
Vancouver Coastal Health
2019
Transnational Press London
2015
Griffith University
2012-2013
The retromer is a trimeric cargo-recognition protein complex composed of Vps26, Vps29 and Vps35 associated with trafficking within endosomes. Recently, pathogenic point mutation the subunit (D620N) was linked to manifestation Parkinson's disease (PD). Here, we investigated details underlying molecular mechanism by which D620N in modulates function, including examination retromer's subcellular localization its capacity sort cargo. We show that expression PD-linked mutant redistributes...
Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play part. The RAB GTPases are regulators and substrates of LRRK2, variants in the LRRK2 gene important for disease. We aimed to explore variability within cases familial
Endosomal sorting is a highly orchestrated cellular process. Retromer heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde of multiple receptors, including cation-independent mannose 6-phosphate receptor for lysosomal enzymes. The cycling retromer on off membrane regulated by network retromer-interacting proteins. Here, we find Parkinson disease-associated Vps35 variant, R524W, but not P316S, loss-of-function mutation as marked reduced association...
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although majority patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 from 34 multi-incident families, which nominated likely pathogenic variants for MS 12 genes innate immune that regulate transcription activation mediators. Rare missense or nonsense were identified...
Biallelic DNAJC12 mutations were described in children with hyperphenylalaninemia, neurodevelopmental delay, and dystonia. We identified homozygous null variants (c.187A>T;p.K63* c.79‐2A>G;p.V27Wfs*14) two kindreds early‐onset parkinsonism. Both probands had mild intellectual disability, nonprogressive, motor symptoms, sustained benefit from small dose of levodopa, substantial worsening symptoms after levodopa discontinuation. Neuropathology (Proband‐A) revealed no alpha‐synuclein...
Abstract Vacuolar protein sorting 35 (VPS35) is a core component of the retromer trimer required for endosomal membrane-associated trafficking. The discovery missense mutation, Vps35 p.D620N implicates dysfunction in pathogenesis Parkinson’s disease (PD). We have characterized knock-in mouse with substitution (hereafter referred to as VKI) at 3 months age. Standardized behavioral testing did not observe overt movement disorder. Tyrosine hydroxylase (TH)-positive nigral neuron counts and...
Objective The aim of this study was to search for genes/variants that modify the effect LRRK2 mutations in terms penetrance and age‐at‐onset Parkinson's disease. Methods We performed first genomewide association disease mutation carriers (776 cases 1,103 non‐cases at their last evaluation). Cox proportional hazard models linear mixed were used identify modifiers mutations, respectively. also investigated whether a polygenic risk score derived from published able explain variability carriers....
Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as subset are both regulators and substrates of LRRK2 kinase. To explore the PD, we undertook comprehensive examination their genetic variability familial PD.Methods: Affected probands from 130 multi-incident families underwent whole-exome sequencing genotyping, Potential...
Abstract Partial phenotypic overlap has been suggested between multiple system atrophy (MSA) and spinocerebellar ataxia 27B, the autosomal dominant caused by an intronic GAA•TTC repeat expansion in FGF14. This study investigated frequency of FGF14 clinically diagnosed pathologically confirmed cases. We screened 657 cases (193 464 confirmed) 1,003 controls. The locus was genotyped using long-range PCR bidirectional repeat-primed PCRs, expansions were with targeted long-read Oxford Nanopore...
Alanine-, serine-, cysteine-preferring transporter 2 (ASCT2, SLC1A5) is responsible for the uptake of glutamine into cells, a major source cellular energy and key regulator mammalian target rapamycin (mTOR) activation. Furthermore, ASCT2 expression has been reported in several human cancers, making it potential both diagnostic therapeutic purposes. Here we identify as membrane-trafficked cargo molecule, sorted through direct interaction with PDZ domain sorting nexin 27 (SNX27). Using...
CAV1 (caveolin 1) expression and secretion is associated with prostate cancer (PCa) disease progression, but the mechanisms underpinning release remain poorly understood. Numerous studies have shown can be secreted within exosome-like vesicles, antibody-mediated neutralization mitigate PCa progression; this suggestive of an inverted (non-exosomal) topology. Here we show that from specific types in vesicle-associated form consistent features bioactive secretion. Characterization isolated...
Abstract Retromer core complex is an endosomal scaffold that plays a critical role in orchestrating protein trafficking within the system. Here we characterized effect of Parkinson's disease‐linked Vps35 D620N endo‐lysosomal system using rescue cell models. fully rescues lysosomal and autophagy defects caused by retromer knock‐out. Analogous to knock out cells, endosome‐to‐trans‐Golgi network transport cation‐independent mannose 6‐phosphate receptor (CI‐M6PR) impaired cells because reduced...
Summary Background Parkinson’s disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as subset are both regulators and substrates of LRRK2 protein kinase. To explore the PD, we undertook comprehensive examination their genetic variability familial PD. Methods Affected probands from 130 multi-incident families underwent whole-exome sequencing genotyping,...
Insulin-stimulated translocation of glucose transporter 4 (GLUT4) storage vesicles (GSVs), the specialized intracellular compartments within mature adipocytes, to plasma membrane (PM) is a fundamental cellular process for maintaining homeostasis. Using 2 independent adipocyte cell line models, human primary Simpson-Golabi-Behmel syndrome and mouse 3T3-L1 fibroblast lines, we demonstrate that endosome-associated protein-sorting complex retromer colocalizes with GLUT4 on GSVs by confocal...
Dysregulation of dopamine neurotransmission profoundly affects motor, motivation and learning behaviors, can be observed during the prodromal phase Parkinson's disease (PD). However, mechanism underlying these pathophysiological changes remains to elucidated. Mutations in vacuolar protein sorting 35 (VPS35) leucine-rich repeat kinase 2 (LRRK2) both lead autosomal dominant PD, VPS35 LRRK2 may physically interact govern trafficking synaptic cargos within endo-lysosomal network a...
Background The excitatory neurotransmitter glutamate has been implicated in both the hyperexcitability required for cortical spreading depression as well activation of trigeminovascular system allodynia associated with migraine. Polymorphisms receptor ionotropic amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionin acid 1 ( GRIA1 ) and GRIA3 genes that code 2 4 subunits have previously migraine an I talian population. In addition, gene is coded within a identified susceptibility locus at X q24....
Leucine-rich repeat kinase 2 (LRRK2) c.6055G>A (p.G2019S) is a frequent cause of Parkinson’s disease (PD), accounting for >30% Tunisian Arab-Berber patients. LRRK2 widely expressed in the immune system and its activity confers survival advantage against infection animal models. Here, we assess haplotype variability cis trans mutation, define age pathogenic allele, explore relationship to onset (AOO), provide evidence positive selection.
Abstract Homozygous DNAJC12 c.79-2A>G (p. V27Wfs*14) loss-of-function mutations were first reported as a cause of young-onset Parkinson’s disease. However, bi-allelic autosomal recessive pathogenic variants in may lead to an alternative constellation neurological features, including infantile dystonia, developmental delay, intellectual disability and neuropsychiatric disorders. is understood co-chaperone aromatic amino acid hydroxylases foster the synthesis biogenic amines. In vitro , we...
Deng et al. report the discovery of TMEM230 c.422G>T (p.Arg141Leu) mutation as a cause late-onset, autosomal dominant Parkinson's disease (PD) 1 in same pedigree which we previously assigned DNAJC13 c.2564A>G (p.Asn855Ser) pathogenic 2. The chromosome 20pter-p12 locus was discovered by short tandem-repeat (STR) genotyping and linkage analysis, with subsequent exome sequencing four affected (II-4, III-1, III-20 III-26) one unaffected family member.Deng state rationale for their re-analysis...
ABSTRACT Introduction : Primary periodic paralyses (PPs) are rare genetic neuromuscular disorders commonly caused by mutations in genes related to ion channel function. However, 10%–20% of cases remain as genetically unexplained. Herein we present a family with PP paralytic episodes generally lasting for 1–7 days at time, associated drop K + levels. Methods Screening known disease‐causing was negative, hence performed whole‐exome sequencing 5 members. Results Minichromosome maintenance...