A5039704196- Ubiquitin and proteasome pathways
- Autophagy in Disease and Therapy
- Protein Degradation and Inhibitors
- Parkinson's Disease Mechanisms and Treatments
- Mitochondrial Function and Pathology
- Cellular transport and secretion
- Genetics and Neurodevelopmental Disorders
- Metabolism, Diabetes, and Cancer
- Lysosomal Storage Disorders Research
- Advanced Proteomics Techniques and Applications
- Amino Acid Enzymes and Metabolism
- Machine Learning in Bioinformatics
- Alzheimer's disease research and treatments
- Cancer-related Molecular Pathways
- Fractal and DNA sequence analysis
- Epigenetics and DNA Methylation
- Genetic and Kidney Cyst Diseases
- RNA Research and Splicing
- Genetic and rare skin diseases.
- Hedgehog Signaling Pathway Studies
- Microtubule and mitosis dynamics
- Tryptophan and brain disorders
- Glycosylation and Glycoproteins Research
- Chronic Lymphocytic Leukemia Research
- Cancer, Hypoxia, and Metabolism
MRC Protein Phosphorylation and Ubiquitylation Unit
2018-2025
Research Network (United States)
2024-2025
University of Dundee
2018-2025
Medical Research Council
2021-2025
Italian Institute of Technology
2016
Azienda Ospedaliero Universitaria San Giovanni Battista
2010
Alzheimer disease (AD) and other tauopathies develop cerebral intracellular inclusions of hyperphosphorylated tau. Epidemiological experimental evidence suggests a clear link between type 2 diabetes mellitus AD. In AD animal models, tau pathology is exacerbated by metabolic comorbidities, such as insulin resistance diabetes. Within this context, anitidiabetic drugs, including the widely-prescribed insulin-sensitizing drug metformin, are currently being investigated for therapy. However,...
Mutations in PINK1 and Parkin result autosomal recessive Parkinson's disease (PD). Cell culture vitro studies have elaborated the PINK1-dependent regulation of defined how this dyad orchestrates elimination damaged mitochondria via mitophagy. phosphorylates ubiquitin at serine 65 (Ser65) an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting activation; however, physiological significance phosphorylation vivo mammals remains unknown. To address this, we...
The reversibility of ubiquitination by the action deubiquitinating enzymes (DUBs) serves as an important regulatory layer within ubiquitin system. Approximately 100 DUBs are encoded human genome, and many have been implicated with pathologies, including neurodegeneration cancer. Non-lysine is chemically distinct, its physiological importance emerging. Here, we couple chemoenzymatically synthesized ubiquitinated lysine threonine model substrates to a mass spectrometry-based DUB assay. Using...
Autosomal recessive mutations in the Parkin gene cause Parkinson's disease. encodes an ubiquitin E3 ligase that functions together with kinase PINK1 a mitochondrial quality control pathway. exists inactive conformation mediated by autoinhibitory domain interfaces. Thus, has become target for development of therapeutics activate its activity. Yet, extent to which different regions can be targeted activation remained unknown. Here, we have used rational structure-based approach design new...
Identification of neuronal targets PD-linked enzyme Parkin by quantitative ubiquitin-based proteomics.
E2-conjugating enzymes (E2s) play a central role in the enzymatic cascade that leads to attachment of ubiquitin substrate. This process, termed ubiquitylation, is required maintain cellular homeostasis and affects almost all process. By interacting with multiple E3 ligases, E2s dictate ubiquitylation landscape within cell. Since its discovery, has been regarded as posttranslational modification specifically targets lysine side chains (canonical ubiquitylation). We used Matrix-Assisted Laser...
The selective removal of dysfunctional mitochondria, a process termed mitophagy, is critical for cellular health and impairments have been linked to aging, Parkinson disease, other neurodegenerative conditions. A central mitophagy pathway orchestrated by the ubiquitin (Ub) kinase PINK1 together with E3 Ub ligase PRKN/Parkin. decoration damaged mitochondrial domains phosphorylated (p-S65-Ub) mediates their elimination though autophagy system. As such p-S65-Ub has emerged as highly specific...
Conserved protein kinases with core cellular functions have been frequently redeployed during metazoan evolution to regulate specialized developmental processes. The Ser/Arg (SR)-rich splicing factor (SRSF) kinase (SRPK), which is implicated in regulation, one such conserved eukaryotic kinase. Surprisingly, we show that SRPK has acquired the capacity control a neurodevelopmental ubiquitin signaling pathway. In mammalian embryonic stem cells and cultured neurons, phosphorylates Ser-Arg motifs...
Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced 1 (PINK1) are associated with familial Parkinson’s disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly Parkin ubiquitin (Ub) indirectly induces phosphorylation of a subset GTPases. Herein we have crossed [R1441C] mutant knock-in mice knock-out (KO) report that loss does not impact endogenous LRRK2-mediated nor do see significant effect on PINK1-mediated Ub...
ABSTRACT Mutations in LRRK2 and PINK1 are associated with familial Parkinson’s disease (PD). phosphorylates Rab GTPases within the Switch II domain whilst directly Parkin ubiquitin indirectly induces phosphorylation of a subset GTPases. Herein we have crossed [R1441C] mutant knock-in mice knock-out (KO) report that loss does not impact endogenous LRRK2-mediated nor do see significant effect on PINK1-mediated phosphorylation. In addition, observe pool Rab-specific, PPM1H phosphatase, is...
Loss-of-function Parkin mutations lead to early-onset of Parkinson’s disease. is an auto-inhibited ubiquitin E3 ligase activated by dual phosphorylation its ubiquitin-like (Ubl) domain and the PINK1 kinase. Herein, we demonstrate a competitive binding phospho-Ubl RING2 domains towards RING0 domain, which regulates activity. We show that phosphorylated can complex with native Parkin, leading activation autoinhibited in trans . Furthermore, activator element (ACT) required maintain enzyme...
Loss-of-function Parkin mutations lead to early-onset of Parkinson's disease. is an auto-inhibited ubiquitin E3 ligase activated by dual phosphorylation its ubiquitin-like (Ubl) domain and the PINK1 kinase. Herein, we demonstrate a competitive binding phospho-Ubl RING2 domains towards RING0 domain, which regulates activity. We show that phosphorylated can complex with native Parkin, leading activation autoinhibited in trans. Furthermore, activator element (ACT) required maintain enzyme...
Parkinsons disease-associated, activating mutations in Leucine Rich Repeat Kinase 2 (LRRK2) block primary cilia formation cholinergic and parvalbumin interneurons astrocytes the striatum, decreasing production of GDNF NRTN neuroprotective factors that normally support dopaminergic neuron viability. We show here 3 month-dietary administration MLi-2 LRRK2 kinase inhibitor restores Hedgehog-responsive by these neurons; are also restored on neurons pedunculopontine nucleus. Importantly, we...
The functional diversity of neurons is specified through their proteome resulting in elaborate and tightly regulated protein interaction networks signalling that regulates neuronal processes. Dysregulation these dynamic development or adulthood lead to neurodevelopmental neurological disorders respectively. Over the past few decades, mass spectrometry has become a powerful tool for quantifying resolving any proteome, including complex tissues such as brain with technological advances leading...
Abstract The reversibility of ubiquitination by the action deubiquitinating enzymes (DUBs) serves as an important regulatory layer within ubiquitin system. Approximately 100 DUBs are encoded human genome and many have been implicated with pathologies including neurodegeneration cancer. Non-lysine is chemically distinct its physiological importance emerging. Here we couple chemoenzymatically synthesized ubiquitinated lysine threonine model substrates to a matrix-assisted laser...
Abstract E2 conjugating enzymes (E2s) play a central role in the enzymatic cascade that leads to attachment of ubiquitin substrate. This process, termed ubiquitylation is fundamental for maintaining cellular homeostasis and impacts almost all process. By interacting with multiple E3 ligases, E2s direct landscape within cell. Since its discovery, has been regarded as post-translational modification specifically targets lysine side chains (canonical ubiquitylation). We used MALDI-TOF Mass...
<title>Abstract</title> Loss of function Parkin mutations lead to early-onset Parkinson’s disease. is an auto-inhibited ubiquitin E3 ligase activated by phosphorylation its ubiquitin-like (Ubl) domain and PINK1. Herein, we show a competitive binding mode the phospho-Ubl RING2 domains on RING0 domain, which regulates activity. We that phosphorylated can directly complex with unmodified Parkin, leading activation autoinhibited in trans. Furthermore, activator element (ACT) required maintain...
<title>Abstract</title> Loss of function Parkin mutations lead to early-onset Parkinson’s disease. is an auto-inhibited ubiquitin E3 ligase activated by phosphorylation its ubiquitin-like (Ubl) domain and PINK1. Herein, we show a competitive binding mode the phospho-Ubl RING2 domains on RING0 domain, which regulates activity. We that phosphorylated can directly complex with unmodified Parkin, leading activation autoinhibited in trans. Furthermore, activator element (ACT) required maintain...
Loss of function Parkin mutations lead to early-onset Parkinson’s disease. is an auto-inhibited ubiquitin E3 ligase activated by phosphorylation its ubiquitin-like (Ubl) domain and PINK1. Herein, we show a competitive binding mode the phospho-Ubl RING2 domains on RING0 domain, which regulates activity. We that phosphorylated can directly complex with unmodified Parkin, leading activation autoinhibited in trans. Furthermore, activator element (ACT) required maintain enzyme’s kinetics, removal...