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Article ; Online: Identifying Biological and Biophysical Features of Different Maturation States of α-Synuclein Amyloid Fibrils.

Skamris, Thomas / Vestergaard, Bente / Madsen, Kenneth L / Langkilde, Annette E / Foderà, Vito

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2551, Page(s) 321–344

Abstract: Protein aggregates, hereunder amyloid fibrils, can undergo a maturation process, whereby early formed aggregates undergo a structural and physicochemical transition leading to more mature species. In the case of amyloid-related diseases, such maturation ... ...

Abstract	Protein aggregates, hereunder amyloid fibrils, can undergo a maturation process, whereby early formed aggregates undergo a structural and physicochemical transition leading to more mature species. In the case of amyloid-related diseases, such maturation confers distinctive biological properties of the aggregates, which may account for a range of diverse pathological subtypes. Here, we present a protocol for the preparation of α-synuclein amyloid fibrils differing in the level of their maturation. We utilize widely accessible biophysical techniques to characterize the structure and morphology and a simple thermal treatment procedure to test their thermodynamic stability. Their biological properties are probed by means of binding to native plasma membrane sheets originating from mammalian cell lines.
MeSH term(s)	Animals ; Humans ; alpha-Synuclein/metabolism ; Amyloid/chemistry ; Protein Aggregates ; Biophysics ; Amyloidosis/metabolism ; Mammals/metabolism
Chemical Substances	alpha-Synuclein ; Amyloid ; Protein Aggregates
Language	English
Publishing date	2022-10-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2597-2_22
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Article ; Online: A density-based enrichment measure for assessing colocalization in single-molecule localization microscopy data.

Ejdrup, Aske L / Lycas, Matthew D / Lorenzen, Niels / Konomi, Ainoa / Herborg, Freja / Madsen, Kenneth L / Gether, Ulrik

Nature communications

2022 Volume 13, Issue 1, Page(s) 4388

Abstract: Dual-color single-molecule localization microscopy (SMLM) provides unprecedented possibilities for detailed studies of colocalization of different molecular species in a cell. However, the informational richness of the data is not fully exploited by ... ...

Abstract	Dual-color single-molecule localization microscopy (SMLM) provides unprecedented possibilities for detailed studies of colocalization of different molecular species in a cell. However, the informational richness of the data is not fully exploited by current analysis tools that often reduce colocalization to a single value. Here, we describe a tool specifically designed for determination of co-localization in both 2D and 3D from SMLM data. The approach uses a function that describes the relative enrichment of one molecular species on the density distribution of a reference species. The function reframes the question of colocalization by providing a density-context relevant to multiple biological questions. Moreover, the function visualize enrichment (i.e. colocalization) directly in the images for easy interpretation. We demonstrate the approach's functionality on both simulated data and cultured neurons, and compare it to current alternative measures. The method is available in a Python function for easy and parameter-free implementation.
MeSH term(s)	Microscopy ; Single Molecule Imaging/methods
Language	English
Publishing date	2022-07-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-32064-y
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Article: Venom-inspired somatostatin receptor 4 (SSTR4) agonists as new drug leads for peripheral pain conditions.

Bjørn-Yoshimoto, Walden E / Ramiro, Iris Bea L / Koch, Thomas Lund / Engholm, Ebbe / Yeung, Ho Yan / Sørensen, Kasper K / Goddard, Carolyn M / Jensen, Kathrine L / Smith, Nicholas A / Martin, Laurent F / Smith, Brian J / Madsen, Kenneth L / Jensen, Knud J / Patwardhan, Amol / Safavi-Hemami, Helena

bioRxiv : the preprint server for biology

2024

Abstract: Persistent pain affects one in five people worldwide, often with severely debilitating consequences. Current treatment options, which can be effective for mild or acute pain, are ill-suited for moderate-to-severe persistent pain, resulting in an urgent ... ...

Abstract	Persistent pain affects one in five people worldwide, often with severely debilitating consequences. Current treatment options, which can be effective for mild or acute pain, are ill-suited for moderate-to-severe persistent pain, resulting in an urgent need for new therapeutics. In recent years, the somatostatin receptor 4 (SSTR One sentence summary: Venom peptides from predatory marine mollusks provide new leads for treating peripheral pain conditions through a non-opioid target.
Language	English
Publishing date	2024-04-30
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.29.591104
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Article ; Online: Behavioral encoding across timescales by region-specific dopamine dynamics.

Jørgensen, Søren H / Ejdrup, Aske L / Lycas, Matthew D / Posselt, Leonie P / Madsen, Kenneth L / Tian, Lin / Dreyer, Jakob K / Herborg, Freja / Sørensen, Andreas T / Gether, Ulrik

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 7, Page(s) e2215230120

Abstract: The dorsal (DS) and ventral striatum (VS) receive dopaminergic projections that control motor functions and reward-related behavior. It remains poorly understood how dopamine release dynamics across different temporal scales in these regions are coupled ... ...

Abstract	The dorsal (DS) and ventral striatum (VS) receive dopaminergic projections that control motor functions and reward-related behavior. It remains poorly understood how dopamine release dynamics across different temporal scales in these regions are coupled to behavioral outcomes. Here, we employ the dopamine sensor dLight1.3b together with multiregion fiber photometry and machine learning-based analysis to decode dopamine dynamics across the striatum during self-paced exploratory behavior in mice. Our data show a striking coordination of rapidly fluctuating signal in the DS, carrying information across dopamine levels, with a slower signal in the VS, consisting mainly of slow-paced transients. Importantly, these release dynamics correlated with discrete behavioral motifs, such as turns, running, and grooming on a subsecond-to-minute time scale. Disruption of dopamine dynamics with cocaine caused randomization of action selection sequencing and disturbance of DS-VS coordination. The data suggest that distinct dopamine dynamics of DS and VS jointly encode behavioral sequences during unconstrained activity with DS modulating the stringing together of actions and VS the signal to initiate and sustain the selected action.
MeSH term(s)	Mice ; Animals ; Dopamine ; Ventral Striatum ; Cocaine ; Reward
Chemical Substances	Dopamine (VTD58H1Z2X) ; Cocaine (I5Y540LHVR)
Language	English
Publishing date	2023-02-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2215230120
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Article ; Online: PICK1-Deficient Mice Maintain Their Glucose Tolerance During Diet-Induced Obesity.

Backe, Marie Balslev / Andersen, Rita Chan / Jensen, Morten / Jin, Chunyu / Hundahl, Cecilie / Dmytriyeva, Oksana / Treebak, Jonas T / Hansen, Jakob Bondo / Gerhart-Hines, Zach / Madsen, Kenneth L / Holst, Birgitte

Journal of the Endocrine Society

2023 Volume 7, Issue 6, Page(s) bvad057

Abstract: Context: Metabolic disorders such as obesity represent a major health challenge. Obesity alone has reached epidemic proportions, with at least 2.8 million people worldwide dying annually from diseases caused by overweight or obesity. The brain-metabolic ...

Abstract	Context: Metabolic disorders such as obesity represent a major health challenge. Obesity alone has reached epidemic proportions, with at least 2.8 million people worldwide dying annually from diseases caused by overweight or obesity. The brain-metabolic axis is central to maintain homeostasis under metabolic stress via an intricate signaling network of hormones. Protein interacting with C kinase 1 (PICK1) is important for the biogenesis of various secretory vesicles, and we have previously shown that PICK1-deficient mice have impaired secretion of insulin and growth hormone. Objective: The aim was to investigate how global PICK1-deficient mice respond to high-fat diet (HFD) and assess its role in insulin secretion in diet-induced obesity. Methods: We characterized the metabolic phenotype through assessment of body weight, composition, glucose tolerance, islet morphology insulin secretion in vivo, and glucose-stimulated insulin secretion ex vivo. Results: PICK1-deficient mice displayed similar weight gain and body composition as wild-type (WT) mice following HFD. While HFD impaired glucose tolerance of WT mice, PICK1-deficient mice were resistant to further deterioration of their glucose tolerance compared with already glucose-impaired chow-fed PICK1-deficient mice. Surprisingly, mice with β-cell-specific knockdown of PICK1 showed impaired glucose tolerance both on chow and HFD similar to WT mice. Conclusion: Our findings support the importance of PICK1 in overall hormone regulation. However, importantly, this effect is independent of the PICK1 expression in the β-cell, whereby global PICK1-deficient mice resist further deterioration of their glucose tolerance following diet-induced obesity.
Language	English
Publishing date	2023-05-16
Publishing country	United States
Document type	Journal Article
ISSN	2472-1972
ISSN (online)	2472-1972
DOI	10.1210/jendso/bvad057
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Article ; Online: Early Stage Alpha-Synuclein Amyloid Fibrils are Reservoirs of Membrane-Binding Species.

Skamris, Thomas / Marasini, Carlotta / Madsen, Kenneth L / Foderà, Vito / Vestergaard, Bente

Scientific reports

2019 Volume 9, Issue 1, Page(s) 1733

Abstract: The presence of αSN fibrils indisputably associates with the development of synucleinopathies. However, while certain fibril morphologies have been linked to downstream pathological phenotypes, others appear less harmful, leading to the concept of fibril ...

Abstract	The presence of αSN fibrils indisputably associates with the development of synucleinopathies. However, while certain fibril morphologies have been linked to downstream pathological phenotypes, others appear less harmful, leading to the concept of fibril strains, originally described in relation to prion disease. Indeed, the presence of fibrils does not associate directly with neurotoxicity. Rather, it has been suggested that the toxic compounds are soluble amyloidogenic oligomers, potentially co-existing with fibrils. Here, combining synchrotron radiation circular dichroism, transmission electron microscopy and binding assays on native plasma membrane sheets, we reveal distinct biological and biophysical differences between initial and matured fibrils, transformed within the timespan of few days. Immature fibrils are reservoirs of membrane-binding species, which in response to even gentle experimental changes release into solution in a reversible manner. In contrast, mature fibrils, albeit macroscopically indistinguishable from their less mature counterparts, are structurally robust, shielding the solution from the membrane active soluble species. We thus show that particular biological activity resides transiently with the fibrillating sample, distinct for one, but not the other, spontaneously formed fibril polymorph. These results shed new light on the principles of fibril polymorphism with consequent impact on future design of assays and therapeutic development.
MeSH term(s)	Amyloid/chemistry ; Amyloid/metabolism ; Amyloid/ultrastructure ; Cell Membrane/metabolism ; Humans ; Protein Aggregation, Pathological/metabolism ; Protein Binding ; Solubility ; Structure-Activity Relationship ; Thermodynamics ; alpha-Synuclein/chemistry ; alpha-Synuclein/metabolism
Chemical Substances	Amyloid ; alpha-Synuclein
Language	English
Publishing date	2019-02-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-38271-2
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Article ; Online: Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment.

Science advances

2024 Volume 10, Issue 9, Page(s) eadg2636

Abstract: Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we use UK Biobank GWAS summary statistics of body mass index (BMI) and body fat percentage (BF% ...

Abstract	Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we use UK Biobank GWAS summary statistics of body mass index (BMI) and body fat percentage (BF%) to identify genes encoding proteins known to interact with postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and
MeSH term(s)	Animals ; Humans ; Mice ; Adaptor Proteins, Signal Transducing/metabolism ; Disks Large Homolog 4 Protein/genetics ; Disks Large Homolog 4 Protein/metabolism ; Genome-Wide Association Study ; Receptors, AMPA/genetics ; Receptors, AMPA/metabolism ; Receptors, Glutamate/genetics ; Receptors, Glutamate/metabolism ; Receptors, N-Methyl-D-Aspartate/genetics
Chemical Substances	Adaptor Proteins, Signal Transducing ; Disks Large Homolog 4 Protein ; Receptors, AMPA ; Receptors, Glutamate ; Receptors, N-Methyl-D-Aspartate ; PICk1 protein, human ; DLG4 protein, human ; Dlg4 protein, mouse ; Prkcabp protein, mouse
Language	English
Publishing date	2024-03-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adg2636
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Article ; Online: Differential Internalization Rates and Postendocytic Sorting of the Norepinephrine and Dopamine Transporters Are Controlled by Structural Elements in the N Termini.

Vuorenpää, Anne / Jørgensen, Trine N / Newman, Amy H / Madsen, Kenneth L / Scheinin, Mika / Gether, Ulrik

The Journal of biological chemistry

2016 Volume 291, Issue 11, Page(s) 5634–5651

Abstract: The norepinephrine transporter (NET) mediates reuptake of synaptically released norepinephrine in central and peripheral noradrenergic neurons. The molecular processes governing availability of NET in the plasma membrane are poorly understood. Here we ... ...

Abstract	The norepinephrine transporter (NET) mediates reuptake of synaptically released norepinephrine in central and peripheral noradrenergic neurons. The molecular processes governing availability of NET in the plasma membrane are poorly understood. Here we use the fluorescent cocaine analogue JHC 1-64, as well as several other approaches, to investigate the trafficking itinerary of NET in live noradrenergic neurons. Confocal imaging revealed extensive constitutive internalization of JHC 1-64-labeled NET in the neuronal somata, proximal extensions and presynaptic boutons. Phorbol 12-myristate 13-acetate increased intracellular accumulation of JHC 1-64-labeled NET and caused a parallel reduction in uptake capacity. Internalized NET strongly colocalized with the "long loop" recycling marker Rab11, whereas less overlap was seen with the "short loop" recycling marker Rab4 and the late endosomal marker Rab7. Moreover, mitigating Rab11 function by overexpression of dominant negative Rab11 impaired NET function. Sorting of NET to the Rab11 recycling compartment was further supported by confocal imaging and reversible biotinylation experiments in transfected differentiated CATH.a cells. In contrast to NET, the dopamine transporter displayed markedly less constitutive internalization and limited sorting to the Rab11 recycling compartment in the differentiated CATH.a cells. Exchange of domains between the two homologous transporters revealed that this difference was determined by non-conserved structural elements in the intracellular N terminus. We conclude that NET displays a distinct trafficking itinerary characterized by continuous shuffling between the plasma membrane and the Rab11 recycling compartment and that the functional integrity of the Rab11 compartment is critical for maintaining proper presynaptic NET function.
MeSH term(s)	Animals ; Cells, Cultured ; Dopamine Plasma Membrane Transport Proteins/analysis ; Dopamine Plasma Membrane Transport Proteins/metabolism ; Endocytosis ; Endosomes/metabolism ; HEK293 Cells ; Humans ; Neurons/cytology ; Neurons/metabolism ; Norepinephrine/metabolism ; Norepinephrine Plasma Membrane Transport Proteins/analysis ; Norepinephrine Plasma Membrane Transport Proteins/metabolism ; Phorbol Esters/metabolism ; Protein Structure, Tertiary ; Protein Transport ; Rats ; Staining and Labeling ; rab GTP-Binding Proteins/analysis ; rab GTP-Binding Proteins/metabolism
Chemical Substances	Dopamine Plasma Membrane Transport Proteins ; Norepinephrine Plasma Membrane Transport Proteins ; Phorbol Esters ; SLC6A2 protein, human ; rab GTP-Binding Proteins (EC 3.6.5.2) ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2016-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M115.702050
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Article ; Online: Coding variants identified in patients with diabetes alter PICK1 BAR domain function in insulin granule biogenesis.

The Journal of clinical investigation

2022 Volume 132, Issue 5

Abstract: Bin/amphiphysin/Rvs (BAR) domains are positively charged crescent-shaped modules that mediate curvature of negatively charged lipid membranes during remodeling processes. The BAR domain proteins PICK1, ICA69, and the arfaptins have recently been ... ...

Abstract	Bin/amphiphysin/Rvs (BAR) domains are positively charged crescent-shaped modules that mediate curvature of negatively charged lipid membranes during remodeling processes. The BAR domain proteins PICK1, ICA69, and the arfaptins have recently been demonstrated to coordinate the budding and formation of immature secretory granules (ISGs) at the trans-Golgi network. Here, we identify 4 coding variants in the PICK1 gene from a whole-exome screening of Danish patients with diabetes that each involve a change in positively charged residues in the PICK1 BAR domain. All 4 coding variants failed to rescue insulin content in INS-1E cells upon knock down of endogenous PICK1. Moreover, 2 variants showed dominant-negative properties. In vitro assays addressing BAR domain function suggested that the coding variants compromised BAR domain function but increased the capacity to cause fission of liposomes. Live confocal microscopy and super-resolution microscopy further revealed that PICK1 resides transiently on ISGs before egress via vesicular budding events. Interestingly, this egress of PICK1 was accelerated in the coding variants. We propose that PICK1 assists in or complements the removal of excess membrane and generic membrane trafficking proteins, and possibly also insulin, from ISGs during the maturation process; and that the coding variants may cause premature budding, possibly explaining their dominant-negative function.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Carrier Proteins/genetics ; Cell Membrane/metabolism ; Diabetes Mellitus/genetics ; Diabetes Mellitus/metabolism ; Humans ; Insulin/genetics ; Insulin/metabolism ; Nerve Tissue Proteins ; Nuclear Proteins/metabolism ; Protein Binding
Chemical Substances	Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Insulin ; Nerve Tissue Proteins ; Nuclear Proteins ; PICk1 protein, human ; amphiphysin (147954-52-7)
Language	English
Publishing date	2022-03-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI144904
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Article ; Online: Development of a Robust Mammalian Cell-based Assay for Studying Recombinant α

Falk-Petersen, Christina B / Søgaard, Rikke / Madsen, Kenneth L / Klein, Anders B / Frølund, Bente / Wellendorph, Petrine

Basic & clinical pharmacology & toxicology

2017 Volume 121, Issue 2, Page(s) 119–129

Abstract: δ-Containing ... ...

Abstract	δ-Containing GABA
Language	English
Publishing date	2017-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2134679-3
ISSN	1742-7843 ; 1742-7835
ISSN (online)	1742-7843
ISSN	1742-7835
DOI	10.1111/bcpt.12778
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