A5062794092- Parkinson's Disease Mechanisms and Treatments
- Nuclear Receptors and Signaling
- RNA regulation and disease
- Alzheimer's disease research and treatments
- Autophagy in Disease and Therapy
- Ubiquitin and proteasome pathways
- Cellular transport and secretion
- Nerve injury and regeneration
- Neurological disorders and treatments
- Peptidase Inhibition and Analysis
- Endoplasmic Reticulum Stress and Disease
- Neuroinflammation and Neurodegeneration Mechanisms
- Mitochondrial Function and Pathology
- Genetic Neurodegenerative Diseases
- Glycosylation and Glycoproteins Research
- biodegradable polymer synthesis and properties
- RNA Interference and Gene Delivery
- Protein Degradation and Inhibitors
- Lysosomal Storage Disorders Research
- Lipid Membrane Structure and Behavior
- Neurological diseases and metabolism
- Biochemical and Structural Characterization
- HIV Research and Treatment
- Bacterial Genetics and Biotechnology
- CRISPR and Genetic Engineering
Biogen (United States)
2016-2024
Light Chain Bioscience (Switzerland)
2009-2018
Brigham and Women's Hospital
2005-2011
Harvard University
2005-2011
National Institutes of Health
2009
National Institute on Aging
2009
École Polytechnique Fédérale de Lausanne
2001-2003
ETH Zurich
2000
Signal peptide peptidase (SPP) catalyzes intramembrane proteolysis of some signal peptides after they have been cleaved from a preprotein. In humans, SPP activity is required to generate sequence–derived human lymphocyte antigen–E epitopes that are recognized by the immune system, and process hepatitis C virus core protein. We identified as polytopic membrane protein with sequence motifs characteristic presenilin-type aspartic proteases. potential eukaryotic homologs may represent another...
Intramembrane proteolysis is a conserved mechanism that regulates variety of cellular processes ranging from transcription control to signaling. In mitochondria, the inner membrane rhomboid protease PARL has been implicated in life span and apoptosis by so far uncharacterized mechanism. Here, we show cleaves human Pink1, which Parkinson's disease, within its anchor. Mature Pink1 then free be released into cytosol or mitochondrial intermembrane space. Upon depolarization potential, canonical...
Recessive mutations in Pink1 lead to a selective degeneration of dopaminergic neurons the substantia nigra that is characteristic Parkinson disease. kinase targeted part mitochondria, and loss function can alter mitochondrial morphology dynamics, thus supporting link between dysfunction disease etiology. Here, we report unbiased identification confirmation multiprotein complex contains Pink1, atypical GTPase Miro, adaptor protein Milton. Our screen also identified an interaction Mitofilin....
No treatments exist to slow or halt Parkinson's disease (PD) progression; however, inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents one the most promising therapeutic strategies. Genetic ablation and pharmacological LRRK2 have demonstrated promise in blocking α-synuclein (α-syn) pathology. However, inhibitors may reduce several tissues induce systemic phenotypes kidney lung that are undesirable. Here, we test whether antisense oligonucleotides (ASOs) provide an...
Abstract Background Pathological and genetic evidence implicates toxic effects of aggregated α‐synuclein in the pathophysiology neuronal dysfunction degeneration Parkinson's disease. Immunotherapy targeting is a promising strategy for delaying disease progression. Objective This study (NCT02459886) evaluated safety, tolerability, pharmacokinetics BIIB054, human‐derived monoclonal antibody that preferentially binds to α‐synuclein, healthy volunteers participants with Methods A total 48 (age...
Aggregation of α-synuclein (α-syn) is neuropathologically and genetically linked to Parkinson's disease (PD). Since stereotypic cell-to-cell spreading α-syn pathology believed contribute progression, immunotherapy with antibodies directed against considered a promising therapeutic approach for slowing progression. Here we report the identification, binding characteristics, efficacy in PD mouse models human-derived antibody BIIB054, which currently under investigation Phase 2 clinical trial...
Parkinson's disease (PD) is a prevalent neurodegenerative with no approved disease-modifying therapies. Multiplications, mutations, and single nucleotide polymorphisms in the SNCA gene, encoding α-synuclein (aSyn) protein, either cause or increase risk for PD. Intracellular accumulations of aSyn are pathological hallmarks Taken together, reduction production may provide therapy We show that antisense oligonucleotides (ASOs) reduce rodent preformed fibril (PFF) models Reduced leads to...
Abstract A key pathological process in Parkinson's disease (PD) is the transneuronal spreading of α‐synuclein. Alpha‐synuclein (α‐syn) a presynaptic protein that, PD, forms inclusions. Other hallmarks PD include neurodegeneration and microgliosis susceptible brain regions. Whether it primarily α‐syn particles, inclusion formation, or other mechanisms, such as inflammation, that cause unclear. We used model induced by striatal injection preformed fibrils into mouse striatum to address this...
Signal sequences of human MHC class I molecules are a unique source epitopes for newly synthesized nonclassical HLA-E molecules. Binding such conserved peptides to induces its cell surface expression and protects cells from NK attack. After cleavage the pre-protein, we show that liberated signal peptide is further processed by peptidase in hydrophobic, membrane-spanning region. This cut essential release epitope-containing fragment lipid bilayer subsequent transport into lumen endoplasmic...
Mutations in the ubiquitously expressed gene PTEN-induced kinase 1 (Pink1) cause autosomal recessive Parkinson's disease. Pink1 encodes a putative serine/threonine with an N-terminal mitochondrial targeting sequence. The mechanism that leads to selective degeneration of dopaminergic neurons via mutations is unknown. A full-length pre-protein (66 kDa) and N-terminally truncated mature form (55 have been described human brain. Here, we report endogenous 66 kDa 55 forms cultured cells are not...
Parkinson disease (PD) has useful symptomatic treatments that do not slow the neurodegenerative process, and no significant disease-modifying are approved. A key therapeutic target in PD is α-synuclein (αS), which both genetically implicated accumulates Lewy bodies rich vesicles other lipid membranes. Reestablishing αS homeostasis a central goal PD. Based on previous lipidomic analyses, we conducted mouse trial of stearoyl-coenzyme desaturase (SCD) inhibitor ("5b") prevented αS-positive...
Significance Parkinson’s disease (PD) is the second most prevalent neurodegenerative of aging, affecting approximately 10 million patients worldwide with no approved therapies to modify progression disease. Further understanding cellular mechanisms contributing development PD necessary discover therapies. Here, we characterize role a recently identified GWAS hit for sporadic PD, ITPKB, in aggregation α-synuclein, primary pathological feature These results identify inhibition...
Presenilin is implicated in the pathogenesis of Alzheimer's disease. It thought to constitute catalytic subunit γ-secretase complex that catalyzes intramembrane cleavage औ-amyloid precursor protein, last step generation amyloidogenic Aऔ peptides. The latter are major constituents amyloid plaques brain disease patients. Inhibitors considered potential therapeutics for treatment this because they prevent production Recently, we discovered a family presenilin-type aspartic proteases. founding...
Signal peptides of secretory and membrane proteins are generated by proteolytic processing precursor after insertion into the endoplasmic reticulum membrane. Liberated signal can be further processed, resulting N-terminal fragments released toward cytosol, where they may interact with target like calmodulin. We show here that requires a protease activity distinct from peptidase. This is inhibited specifically newly developed cysteine inhibitor,...
The human genome encodes seven intramembrane-cleaving GXGD aspartic proteases. These are the two presenilins that activate signaling molecules and implicated in Alzheimer's disease, signal peptide peptidase (SPP), required for immune surveillance, four SPP-like candidate proteases (SPPLs), of unknown function. Here we describe a comparative analysis topologies SPP its homologues, SPPL2a, -2b, -2c, -3. We demonstrate their N-terminal extensions located extracellular space and, except SPPL3,...
Autosomal-recessive mutations in the Parkin gene are second most common cause of familial Parkinson's disease (PD). deficiency leads to premature demise catecholaminergic neurons ventral midbrain PD. Thus, a better understanding parkin function may elucidate molecular aspects their selective vulnerability idiopathic Numerous lines evidence suggest mitochondrial for and protective effect ectopic expression. Since mitochondria play critical role cell survival/cell death through regulated...
Abstract Huntington's disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the HTT gene. In addition to germline expansions, somatic neurons also contribute HD pathogenesis. The DNA mismatch repair gene, MSH3, identified as genetic modifier onset and progression, promotes thus presents potential therapeutic target. However, what extent MSH3 protein reduction needed attenuate elicit benefits models less clear. our study, we...
Significance The mechanisms responsible for brain α-synuclein (αS) dyshomeostasis, caused by Gaucher’s GBA1 mutations that increase Parkinson’s disease (PD) risk, are largely unknown. We previously showed abrogating physiological αS tetramers a familial PD-E46K–amplified 3K mutation produces PD-like syndrome in mice and treatment with stearoyl-CoA desaturase inhibitors increased portion of the tetramers, benefitting motor phenotypes. Here, we show that—similar to previous findings...
Pharmacological activation of the E3 ligase Parkin represents a rational therapeutic intervention for treatment Parkinson's disease. Here we identify several compounds that enhance activity wildtype in presence phospho-ubiquitin and act as positive allosteric modulators (PAMs). While these activate series biochemical assays, they do not by thermally destabilizing fail to translocation rate mitochondria or enact mitophagy cell-based assays. We conclude context cellular milieu window...
Through its pathological and genetic association to Parkinson9s Disease (PD), α-synuclein (α-syn) remains a favorable therapeutic target that is being investigated using various modalities, including many passive immunotherapy approaches clinically targeting different forms of α-syn epitopes. Whereas published studies from some trials have demonstrated engagement in plasma, none shown direct drug-antigen interactions the disease-relevant compartment, central nervous system (CNS). Cinpanemab...
Objective: The primary objective was to evaluate the safety, tolerability and pharmacokinetics of BIIB054, a human-derived monoclonal antibody that preferentially binds aggregated forms alpha-synuclein in patients with Parkinson’s disease (PD). Background: Progression PD is related spread alpha-synuclein–containing intraneuronal inclusions (Lewy bodies neurites). It suggested cell-to-cell transmission species underlying mechanism for pathological Lewy pathology brain. Thus, immunotherapy...