Article
Clinical Neurology
P. La Vitola, C. Balducci, M. Baroni, L. Artioli, G. Santamaria, M. Castiglioni, M. Cerovic, L. Colombo, L. Caldinelli, L. Pollegioni, G. Forloni
Summary: The study demonstrates that peripherally induced neuroinflammation can potentiate the detrimental effects of alpha-synuclein oligomers and worsen cognitive deficits in A53T mice. Fine management of neuroinflammation may offer a promising therapeutic approach to prevent or slow down some behavioral aspects in alpha-synucleinopathies.
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
(2021)
Review
Clinical Neurology
Wouter Peelaerts, Veerle Baekelandt
Summary: Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are synucleinopathies characterized by the intracellular aggregation of alpha-synuclein. The cellular tropism of synuclein pathology differs in these disorders, with PD and DLB showing aggregates in neurons and MSA showing aggregates in oligodendrocytes. Studies have found unique molecular signatures of fibrillar alpha-synuclein in experimental models and human brain, suggesting that the structure of these fibrils may be influenced by their cellular environment. The cellular host environment and in vivo transmission routes may play a role in the development of alpha-synuclein strains. This finding has implications for preclinical studies and the development of biomarkers and therapeutic strategies.
Article
Biochemistry & Molecular Biology
Seo-Jun Kang, Soo-Jeong Kim, Hye Rin Noh, Beom Jin Kim, Jae-Bong Kim, Uram Jin, Sun Ah Park, Sang Myun Park
Summary: In this study, the role of neuronal ApoE in the cell-to-cell transmission of alpha-synuclein (alpha-syn) was evaluated. It was found that ApoE deficiency attenuates alpha-syn uptake and release, thereby contributing to its propagation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Roberta Cascella, Serene W. Chen, Alessandra Bigi, Jose D. Camino, Catherine K. Xu, Christopher M. Dobson, Fabrizio Chiti, Nunilo Cremades, Cristina Cecchi
Summary: The self-assembly of alpha-synuclein (alpha S) is a pathological feature of Parkinson's disease. The authors demonstrate that alpha S fibrils release soluble prefibrillar oligomeric species responsible for neurotoxicity in vitro.
NATURE COMMUNICATIONS
(2021)
Article
Neurosciences
Dorit Trudler, Sara Sanz-Blasco, Yvonne S. Eisele, Swagata Ghatak, Karthik Bodhinathan, Mohd Waseem Akhtar, William P. Lynch, Juan C. Pina-Crespo, Maria Talantova, Jeffery W. Kelly, Stuart A. Lipton
Summary: In Parkinson's disease, synaptic and neuronal loss are prominent features. The study reveals that alpha Syn oligomers induce excessive glutamate release from astrocytes, activating NMDARs on neurons and leading to synaptic damage. However, the drug NitroSynapsin shows promise in protecting synapses from alpha Syn-induced damage.
JOURNAL OF NEUROSCIENCE
(2021)
Article
Neurosciences
Brent J. Ryan, Nora Bengoa-Vergniory, Matthew Williamson, Ecem Kirkiz, Rosalind Roberts, Gabriele Corda, Maximilian Sloan, Saba Saqlain, Marta Cherubini, Josse Poppinga, Helle Bogtofte, Milena Cioroch, Svenja Hester, Richard Wade-Martins
Summary: The accumulation of alpha-synuclein oligomers leads to dopaminergic neuronal-specific dysfunction through mitochondrial toxicity, which can be attenuated by REST in an early model of Parkinsonian pathology. This finding highlights REST as a mediator of dopaminergic vulnerability in Parkinson's disease.
JOURNAL OF NEUROSCIENCE
(2021)
Article
Chemistry, Multidisciplinary
Saurabh Awasthi, Cuifeng Ying, Jiali Li, Michael Mayer
Summary: This study demonstrates that resistive pulse measurements using polymer-coated solid-state nanopores enable single-particle-level characterization of the size and shape of individual amyloid oligomers in solution. Compared with conventional approaches, nanopore-based characterization provides superior resolution and rapid analysis in solution, which has the potential to become a widely accessible technique.
Article
Multidisciplinary Sciences
Satra Nim, Darren M. O'Hara, Carles Corbi-Verge, Albert Perez-Riba, Kazuko Fujisawa, Minesh Kapadia, Hien Chau, Federica Albanese, Grishma Pawar, Mitchell L. De Snoo, Sophie G. Ngana, Jisun Kim, Omar M. A. El-Agnaf, Enrico Rennella, Lewis E. Kay, Suneil K. Kalia, Lorraine V. Kalia, Philip M. Kim
Summary: This study demonstrates that disruption of the interaction between CHMP2B and alpha-synuclein by a peptide inhibitor can alleviate neurodegeneration in Parkinson's disease models. The accumulation of alpha-synuclein and its toxic forms is implicated in dopaminergic neurodegeneration. The peptide inhibitor identified in this study restores endolysosomal function and reduces alpha-synuclein levels in various models, suggesting that targeting the alpha-synuclein-CHMP2B interaction could be a potential therapeutic strategy.
NATURE COMMUNICATIONS
(2023)
Article
Medicine, General & Internal
Angelo M. Jamerlan, Seong Soo A. An
Summary: In this study, the interaction between TDP-43 and alpha-synuclein was investigated using a solid-phase microplate-based immunoassay. The results showed that a region of the low complexity domain of TDP-43 interacts with full-length alpha-synuclein. This method provides a convenient, economical, and rapid way to locate antibody epitopes and interaction sites of two proteins.
JOURNAL OF CLINICAL MEDICINE
(2022)
Review
Biochemistry & Molecular Biology
Jaime Santos, Irantzu Pallares, Salvador Ventura
Summary: This review focuses on the structural and mechanistic characterization of alpha-S synuclein oligomers, which are considered key pathogenic factors in synucleinopathies. Recent advances in understanding these elusive species have paved the way for targeting therapeutics and diagnosis.
Article
Biochemistry & Molecular Biology
Camilla B. Andersen, Astrid K. Lausdahl, Janni Nielsen, Mathias P. Clausen, Frans A. A. Mulder, Daniel E. Otzen, Eva C. Arnspang
Summary: Oxidative stress and the formation of cytotoxic oligomers by the natively unfolded protein & alpha;-synuclein (& alpha;-syn) are implicated in the development of Parkinson's disease. However, the specific mechanisms underlying these processes are still unclear. In this study, & alpha;-syn oligomers (& alpha;SOs) were prepared in vitro in the presence of a lipid peroxidation product, and their interaction with live cells was investigated using advanced microscopy techniques. The results demonstrate that the cytotoxic & alpha;-syn aggregates closely interact with cellular membranes and organelles, providing direct evidence for their involvement in cellular dysfunction associated with Parkinson's disease.
Review
Biochemistry & Molecular Biology
Cecilia Chavarria, Rodrigo Ivagnes, Jose M. Souza
Summary: This review article discusses the mechanisms and processes associated with alpha-synuclein uptake in glial cells and the resulting neuronal death.
Review
Biochemistry & Molecular Biology
Greta Musteikyte, Akhila K. Jayaram, Catherine K. Xu, Michele Vendruscolo, Georg Krainer, Tuomas P. J. Knowles
Summary: Parkinson's disease is an incurable neurodegenerative disorder characterized by the formation of Lewy bodies. Oligomeric forms of the protein alpha-synuclein interacting with lipid membranes are considered the main pathogenic species. Understanding the structural and biophysical features of these oligomers and their interactions with membranes is crucial for deciphering the etiology of Parkinson's disease and its toxicity in vivo.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2021)
Article
Biochemistry & Molecular Biology
Laxmikant Gadhe, Arunima Sakunthala, Semanti Mukherjee, Nitisha Gahlot, Riya Bera, Ajay Singh Sawner, Pradeep K. Kadu, Samir Maji
Summary: Although the pathogenic mechanism of synucleinopathies, including Parkinson's disease (PD), is not fully understood, α-synuclein (α-Syn) oligomers may play a significant role in the pathogenesis of PD. These oligomers are neurotoxic and may cause neuronal cell death. However, studying the structure and mechanisms of these oligomers is challenging due to their heterogeneity and transient nature. Understanding the formation and role of α-Syn oligomers can contribute to the development of new therapeutic approaches for PD.
BIOPHYSICAL CHEMISTRY
(2022)
Article
Chemistry, Analytical
Chia-Ming Yang, Jia-Yuan Chang, Min-Yi Chen, Chao-Sung Lai
Summary: This study systematically investigates portable and low-cost platforms for the early detection of biomarkers of Parkinson's disease using the Proton-enzyme-linked immunosorbent assay (Proton-ELISA) methodology. The results show that the Proton-ELISA platform performs better than conventional ELISA kits in detecting the alpha-synuclein antigen. Proton-ELISA can be suggested for specific applications requiring less degradation or interference.
Article
Multidisciplinary Sciences
Harm Ruesink, Lasse Reimer, Emil Gregersen, Arne Moeller, Cristine Betzer, Poul Henning Jensen
Article
Neurosciences
Rikke H. Kofoed, Cristine Betzer, Nelson Ferreira, Poul Henning Jensen
NEUROBIOLOGY OF DISEASE
(2020)
Article
Neurosciences
Sara Elfarrash, Nanna Moller Jensen, Nelson Ferreira, Cristine Betzer, Jervis Vermal Thevathasan, Robin Diekmann, Mohamed Adel, Nisreen Mansour Omar, Mohamed Z. Boraie, Sabry Gad, Jonas Ries, Deniz Kirik, Sadegh Nabavi, Poul Henning Jensen
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2019)
Article
Clinical Neurology
Lasse Reimer, Cristine Betzer, Rikke Hahn Kofoed, Christiane Volbracht, Karina Fog, Chaitanya Kurhade, Emma Nilsson, Anna K. Overby, Poul Henning Jensen
Summary: The abnormal phosphorylation of tau protein, mediated by PKR kinase, plays a crucial role in the pathogenesis of tauopathies like Alzheimer's disease. PKR can directly phosphorylate tau at specific residues, leading to its displacement from microtubules and dysregulation of gene expression, particularly during acute brain inflammation.
Article
Multidisciplinary Sciences
Danielle Weber-Adrian, Rikke Hahn Kofoed, Joseph Silburt, Zeinab Noroozian, Kairavi Shah, Alison Burgess, Shawna Rideout, Sebastian Kuegler, Kullervo Hynynen, Isabelle Aubert
Summary: Non-surgical gene delivery to the brain using AAV6-syn-GFP with MRIgFUS resulted in lower off-target biodistribution in the liver compared to AAV9 and AAV1&2, while providing neuronal GFP expression in the striatum and hippocampus.
SCIENTIFIC REPORTS
(2021)
Article
Clinical Neurology
Kristiana Xhima, Kelly Markham-Coultes, Rikke Hahn Kofoed, H. Uri Saragovi, Kullervo Hynynen, Isabelle Aubert
Summary: Early degeneration of basal forebrain cholinergic neurons plays a crucial role in cognitive decline in Alzheimer's disease. Therapeutic benefits of nerve growth factor (NGF) in neuroprotection and cognitive function remain unresolved in the presence of Alzheimer's disease-related pathologies. MRI-guided focused ultrasound (MRIgFUS) can enhance delivery of TrkA agonists to targeted brain areas and potentially counteract Alzheimer's disease-related vulnerability.
Article
Medicine, Research & Experimental
Rikke Hahn Kofoed, Stefan Heinen, Joseph Silburt, Sonam Dubey, Chinaza Lilian Dibia, Miriam Maes, Elizabeth M. Simpson, Kullervo Hynynen, Isabelle Aubert
Summary: Efficient gene delivery to the brain using new technologies could provide potential treatments for Alzheimer's disease, although immunological responses will need to be carefully considered.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2021)
Article
Chemistry, Multidisciplinary
Rikke Hahn Kofoed, Chinaza Lilian Dibia, Kate Noseworthy, Kristiana Xhima, Nathalie Vacaresse, Kullervo Hynynen, Isabelle Aubert
Summary: Focused ultrasound combined with intravenously injected microbubbles (FUS) can increase the permeability of the blood-brain barrier (BBB) and deliver genes to the brain. The properties of AAV serotypes and targeted brain tissue influence the distribution, diffusion, and transduction of AAVs. Non-invasive contrast-enhanced MR imaging can predict the efficacy of FUS-AAV delivery.
JOURNAL OF CONTROLLED RELEASE
(2022)
Article
Medicine, Research & Experimental
Rikke Hahn Kofoed, Kate Noseworthy, Kathleen Wu, Shuruthisai Sivadas, Lisa Stanek, Bradford Elmer, Kullervo Hynynen, Lamya S. Shihabuddin, Isabelle Aubert
Summary: Magnetic resonance imaging-guided focused ultrasound combined with microbubbles injected in the bloodstream (MRIgFUS) temporarily increases the permeability of the blood-brain barrier (BBB), facilitating the delivery of adeno-associated viruses (AAVs) to targeted brain areas. By using AAV2-HBKO as a vector, MRIgFUS-mediated delivery of AAVs shows broader gene distribution in the brain and higher expression in neurons compared to AAV9. This method has the potential to achieve functionally and clinically relevant gene delivery to the brain.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2022)
Article
Biochemistry & Molecular Biology
Rikke Hahn Kofoed, Elizabeth M. Simpson, Kullervo Hynynen, Isabelle Aubert
Summary: Transcranial ultrasound combined with intravenous microbubbles can increase blood-brain barrier permeability or mediate sonoselective gene delivery to endothelial cells. However, the use of recombinant adeno-associated virus 9 (rAAV9) did not significantly enhance transgene expression in brain endothelial cells compared to plasmid delivery. This suggests that intravenous rAAV9 utilizes different mechanisms for entering the cerebrovasculature than plasmids coated onto microbubbles.
Article
Clinical Neurology
Sindhu Menon, Rikke H. Kofoed, Fadl Nabbouh, Kristiana Xhima, Yasmeen Al-Fahoum, Tammy Langman, Howard T. J. Mount, Lamya S. Shihabuddin, S. Pablo Sardi, Paul E. Fraser, Joel C. Watts, Isabelle Aubert, Anurag Tandon
Summary: The study demonstrates that AAV1-mediated expression of microRNA targeting the alpha-synuclein gene can significantly reduce motor deficits and pathology in mice induced by an injection of synucleinopathy-affected brain homogenates. Partial suppression of alpha-synuclein is enough to prevent pathology spreading to distal brain regions with normal levels. Silencing alpha-synuclein gene expression can reduce native non-aggregated alpha-synuclein substrate and disrupt the propagation of pathological alpha-synuclein.
BRAIN COMMUNICATIONS
(2021)
Meeting Abstract
Biotechnology & Applied Microbiology
R. H. Kofoed, C. L. Dibia, K. Noseworthy, K. Xhima, N. Vacaresse, L. Stanek, B. Elmer, L. Shihabuddin, K. Hynynen, I. Aubert
HUMAN GENE THERAPY
(2021)
Meeting Abstract
Biotechnology & Applied Microbiology
Rikke H. Kofoed, Kate Noseworthy, Chinaza Dibia, Nathalie Vacaresse, Kullervo Hynynen, Isabelle Aubert
Article
Medicine, Research & Experimental
Yacine Touahri, Rajiv Dixit, Rikke Hahn Kofoed, Kristina Miloska, EunJee Park, Reza Raeisossadati, Kelly Markham-Coultes, Luke Ajay David, Hibo Rijal, Jiayi Zhao, Madelaine Lynch, Kullervo Hynynen, Isabelle Aubert, Carol Schuurmans
