MAP1LC3A

Researchers describe a natural product-like molecule, Tantalosin, that inhibits interaction between two proteins in complexes that reshape membranes inside the cell. The findings lead to a deeper understanding of how membrane remodeling works in human cells and future development of new drugs. In a study published in PNAS, Umeå researchers describe a natural product-like molecule, Tantalosin, that inhibits interaction between two proteins in complexes that reshape membranes inside the cell. The findings lead to a deeper understanding of how membrane remodelling works in human cells and future development of new drugs. "Our study is a good case to use small molecules as valuable chemical tools for understanding complex biological mechanisms. I am happy to coordinate a fantastic collaboration with colleagues in Umeå, Stockholm and Germany," says Yaowen Wu, professor at the Department of Chemistry at Umeå University. Membranes of cells are made of lipids and proteins, and they serve barrier functions for cells and intracellular organelles. Membranes of cells are highly dynamic mosaic-fluid structures that undergo constant reshaping. The endosomal sorting complex required for transport (ESCRT) is tasked with remodelling membranes inside the cell. The ESCRT machinery assembles at the site in the cell where membranes need deformation and then forms helical protein polymers that can contract and pinch off cell membranes. Previously, Professor Yaowen Wu and his group, in collaboration with Professor Herbert Waldmann's laboratory at Max Planck Institute Dortmund in Germany, identified a chemical molecule, Tantalosin, that induces a phenotype like autophagy -- a self-eating process in the cell. Tantalosin is a synthetic molecule inspired by alkaloids from the medical plant Cinchona. They observed a very interesting phenomenon in the cell treated with Tantalosin and investigated further the molecular mechanism how Tantalosin works in the cell. In collaboration with the chemical proteomics core facility at SciLifeLab in Karolinska Institute the team scrutinized potential cellular targets of Tantalosin. "To our surprise, we found that none of the autophagy-related proteins were on the list of potential targets. However, IST1 protein in ESCRT complexes was identified and validated as the cellular target of Tantalosin. We were excited to work on deciphering this unexpected connection between ESCRT complexes and autophagy," says first author Anastasia Knyazeva, who just recently completed her doctoral degree at the Department of Chemistry at Umeå University. The researchers characterized the mechanism using a range of biochemical and cell biological methods. When they studied protein-protein interaction in solution, they found that Tantalosin completely stops the interaction between IST1 and its binding partner CHMP1B. "We then took a closer look at these two proteins using a transmission electron microscope in collaboration with Kasturika Shankar, a PhD student from Lars-Anders Carlson's lab at Umeå University. Intriguingly, Tantalosin disrupts the formation of ordered IST1-CHMP1B filaments," explains Shuang Li, the paper's co-first author and postdoctoral fellow at the Department of Chemistry at Umeå University. Furthermore, the researchers looked inside the cell and found that Tantalosin rapidly disrupts the recycling of cell-surface receptors back to the cell surface. This property could be potentially beneficial for treating certain types of cancers that are driven by cell-surface receptors. In this study, the researchers found that LC3 protein, which is usually a hallmark of autophagy, is linked to the endosomal membranes during Tantalosin treatment. Interestingly, the canonical autophagic degradation was not observed. Instead, they found that the process follows a noncanonical autophagy pathway. "We believe that Tantalosin can be a unique molecule that facilitates understanding new functions of noncanonical conjugation of LC3 to endosomal membranes. We hope that further studies will reveal the role of LC3-membrane conjugation and its associated proteins in membrane deformation processes," says Anastasia Knyazeva.

Statistically significant decreased levels of novel biomarker AGO2 (p= 0.002) observed in newly diagnosed people living with Parkinson's disease (PD) compared to healthy individuals NeuroSense's combination platform has been observed in a clinical trial to induce an increase of AGO2 in ALS patients, indicating therapeutic potential in PD NeuroSense is exploring co-development of PD asset with potential collaborators CAMBRIDGE, Mass., May 2, 2023 /PRNewswire/ -- NeuroSense Therapeutics Ltd. (Nasdaq: NRSN) ("NeuroSense"), a company developing treatments for severe neurodegenerative diseases, today announced positive preliminary results from a novel biomarker study conducted to evaluate the potential of NeuroSense's combination platform therapy for the treatment of Parkinson's disease (PD), the second most common neurodegenerative disorder. This study compared blood samples from 30 healthy individuals to 30 people living with PD by utilizing neuronal derived exosomes to identify modulations in PD-associated biomarkers, including AG02. AGO2 (Argonaute 2), the catalytic subunit of the protein complex responsible for RNA-induced silencing,1 was shown to be critical to the regulation of alpha-synuclein (αSyn) accumulation in dopaminergic neurons of the substantia nigra pars compacta, the region of the brain that is responsible for motor control.2 The dysregulation of αSyn through dysfunction of AGO2 can have detrimental effects in the brain, which can lead to PD. In the PD biomarker study, NeuroSense observed a statistically significant (p= 0.002) decrease in levels of AGO2 in newly diagnosed PD patients (n=15) when compared to the healthy control group. There were no significant changes observed in AGO2 levels of more advanced stage PD patients, indicating this trend could be related to disease onset. In a Phase 2a clinical trial conducted in people living with amyotrophic lateral sclerosis (ALS), NeuroSense's platform combination therapy was observed to induce a statistically significant (p= 0.039) increase of AGO2 and also showed a trend of increased levels of LC3 (p= 0.054). LC3 is an essential protein involved in autophagy,3 a cellular recycling process utilized to degrade aggregated proteins and damaged organelles, which has been reported to be involved in many neurodegenerative disorders, including PD. In the PD biomarker study NeuroSense observed a change in levels of LC3, which decreased in newly diagnosed PD patients (p= 0.034), suggesting an impairment in cellular recycling processes. Other biomarkers that were measured, including some PD-specific markers, did not reveal trends and may be revisited in future studies. "We believe these results strengthen the scientific rationale to develop NeuroSense's platform technology for PD, as the mechanism of action may be helpful in targeting disease-specific pathways, specifically AGO2 dysregulation," stated Dr. Shiran Zimri, NeuroSense's VP of R&D. "We intend to further evaluate these findings, as well as explore additional biomarkers and their involvement in the progression and pathology of PD in future studies." Prof. Roy Alcalay M.D., Chief of the Movement Disorders Center at Tel-Aviv Sourasky Medical Center, who participated in conducting the PD biomarker study, commented, "We are excited by this interesting collaboration and look forward to continuing our work together." "We believe that these data denote the potential of NeuroSense's platform technology to target early stages of Parkinson's disease. This is particularly relevant as early detection of PD is becoming more common," stated NeuroSense's CEO, Alon Ben-Noon. "Based on these encouraging results, we are now looking to co-develop our PD asset with collaborators that have a core focus on Parkinson's." About Parkinson's Disease Parkinson's disease (PD) is the second most common neurogenerative condition after Alzheimer's disease. Nearly 1 million people in the U.S. and an estimated 10 million people worldwide are living with PD. Characterized by uncontrollable movements, difficulty with balance and coordination, as well fatigue, depression, and memory difficulties, these symptoms begin to occur when dopaminergic neurons in the substantia nigra become impaired and die. The global PD treatment market was valued at $5.7 billion in 2021 and is projected to reach $10.4 billion by 2031, growing at a CAGR of 6.2%. About AGO2 AGO2 is a protein-coding gene essential for miRNA function. It is involved in the regulation of alpha-synuclein (αSyn) biogenesis. As obtained in cultures and cell tissues alike, depletion of AGO2 leads to αSyn accumulation. In pre-clinical studies, an increase in αSyn mRNA and protein expression was observed when AGO2 is knocked-out. The dysregulation of αSyn through dysfunction of AGO2 can have detrimental effects in the brain, resulting in PD.2 About LC3 LC3, microtubule-associated protein 1A/1B-light chain 3, is an essential protein involved in autophagosome biogenesis/maturation, as well as an adaptor protein for selective autophagy.3 The most prevalent pathological features of many neurodegenerative diseases are the aggregation of misfolded proteins and the loss of neurons. Autophagy, utilized to degrade aggregated proteins and damaged organelles, has been reported to be involved in the occurrence of pathological changes in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS).4Therefore, LC3 has been widely used to monitor the number of autophagosomes as well as autophagic activity.3 About NDEs NeuroSense's biomarker study utilized neuronal-derived exosomes (NDEs) extracted from plasma. NDEs are small extracellular vesicles (EVs) generated by neurons that encapsulate a variety of molecules such as proteins, nucleic acids, and metabolites. ExoSORT™ by NeuroDex was used to identify NDEs in this biomarker study. Identification of NDEs and their cargo in body fluids can facilitate the discovery of new biomarkers for prognosis and therapy, as these vesicles can pass the blood-brain barrier (BBB) and provide a depiction of the current physiological status of neurons in the brain. About NeuroSense NeuroSense Therapeutics, Ltd. is a clinical-stage biotechnology company focused on discovering and developing treatments for patients suffering from debilitating neurodegenerative diseases. NeuroSense believes that these diseases, which include amyotrophic lateral sclerosis (ALS), Alzheimer's disease and Parkinson's disease, among others, represent one of the most significant unmet medical needs of our time, with limited effective therapeutic options available for patients to date. Due to the complexity of neurodegenerative diseases and based on strong scientific research on a large panel of related biomarkers, NeuroSense's strategy is to develop combined therapies targeting multiple pathways associated with these diseases. For additional information, we invite you to visit our website and follow us on LinkedIn and Twitter. Forward-Looking Statements This press release contains "forward-looking statements" that are subject to substantial risks and uncertainties. All statements, other than statements of historical fact, contained in this press release are forward-looking statements. Forward-looking statements contained in this press release may be identified by the use of words such as "anticipate," "believe," "contemplate," "could," "estimate," "expect," "intend," "seek," "may," "might," "plan," "potential," "predict," "project," "target," "aim," "should," "will" "would," or the negative of these words or other similar expressions, although not all forward-looking statements contain these words. Forward-looking statements are based on NeuroSense Therapeutics' current expectations and are subject to inherent uncertainties, risks and assumptions that are difficult to predict and include statements regarding the co-development of our PD assets with collaborators with a core focus on Parkinson's. Further, certain forward-looking statements are based on assumptions as to future events that may not prove to be accurate. Forward-looking statements are subject to a number of risks and uncertainties, including a delay in the reporting of top-line results from our ALS Phase 2b clinical trial, the risk that the final results of Parkinson's Disease (PD) Biomarker Study will not be consistent with the preliminary results and the risk that we will not be successful in signing co-development agreement or other agreements with collaborators with a core focus on Parkinson's. The future events and trends may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward looking statements. You should not rely on these statements as representing our views in the future. More information about the risks and uncertainties affecting the Company is contained under the heading "Risk Factors" in the Annual Report on Form 20-F filed with the Securities and Exchange Commission on March 22, 2023. Forward-looking statements contained in this announcement are made as of this date, and NeuroSense Therapeutics Ltd. undertakes no duty to update such information except as required under applicable law. 1 O'Carroll, D. & Schaefer, A. General Principals of miRNA Biogenesis and Regulation in the Brain. Neuropsychopharmacology 38, 39-54, doi:10.1038/npp.2012.87 (2013). 2 Hernandez, S. M. et al. Unexpected Implication of SRP and AGO2 in Parkinson's Disease: Involvement in Alpha-Synuclein Biogenesis. Cells 10, doi:10.3390/cells10102792 (2021). 3 Lee, Y. K. & Lee, J. A. Role of the mammalian ATG8/LC3 family in autophagy: differential and compensatory roles in the spatiotemporal regulation of autophagy. BMB reports 49, 424-430, doi:10.5483/bmbrep.2016.49.8.081 (2016). 4 Guo, F., Liu, X., Cai, H. & Le, W. Autophagy in neurodegenerative diseases: pathogenesis and therapy. Brain pathology (Zurich, Switzerland) 28, 3-13, doi:10.1111/bpa.12545 (2018). Company Codes: NASDAQ-NMS:NRSN

The Nucleus 8 Sound Processor is the world's first cochlear implant sound processor ready for Bluetooth LE Audio technology LONE TREE, Colo., Nov. 1, 2022 /PRNewswire/ -- Cochlear Limited (ASX: COH), the global leader in implantable hearing solutions, receives U.S. Food and Drug Administration (FDA) approval for the Cochlear™ Nucleus® 8 Sound Processor. The Nucleus 8 Sound Processor is now the smallest and lightest behind-the-ear cochlear implant sound processor available in the industry. 1-3 It is also the world's first cochlear implant sound processor ready to provide direct audio connectivity to everyday consumer electronics using the next generation LE Audio technology from Bluetooth®.1-3,# Experience the full interactive Multichannel News Release here: The Nucleus 8 Sound Processor features Cochlear's latest and most innovative hearing technology that can sense changes in a person's environment and automatically adjust their listening settings.4-7* It also includes an enhanced ForwardFocus+ feature, which effectively reduces distracting background noise to make face-to-face conversations clearer, especially in noisy environments.8,^ Cochlear continues its commitment to reduce the size of each processor generation with the new behind-the-ear sound processor being 15 percent smaller and 13 percent lighter than its predecessor.9, ± For more on the Nucleus 8 Sound Processor, visit . "Cochlear's goal is to help people feel empowered to connect with their world and make it easier to hear and be heard," said Lisa Aubert, President, Cochlear Americas. "In a restaurant, at work, at school, or spending time with family and friends – life's full of opportunities to engage with others. The Nucleus 8 Sound Processor is our smallest, lightest and smartest behind-the-ear sound processor yet and is designed to help people hear conversations more clearly and comfortably, wherever life may take them." Smaller, smarter and better connected The Nucleus 8 Sound Processor builds on the direct streaming capabilities available in Cochlear's latest sound processors. With access to next-generation Bluetooth LE Audio, it will be easier than ever to directly connect to everyday technology in more places and from more devices than ever before.10-12,# People will be able to conveniently connect directly to broadcasts at public venues such as airports, conference centers, sport stadiums and gyms that support Bluetooth's next generation Auracast™. "Cochlear continues to lead in innovation that matters most, delivering smaller and smarter sound processors to improve hearing performance that's comfortable and easy to use," said Ryan Lopez, Director, Nucleus Product Management & Marketing, Cochlear Americas. "The Bluetooth LE Audio connectivity in the Nucleus 8 Sound Processor will provide those with hearing loss new, more convenient ways to stream audio to their sound processor, including making it easier for children and adults to engage in the world around them. From the classroom to the conference room, we want to help reduce the stress of life's interactions with the Nucleus 8 Sound Processor." In addition to the Nucleus 8 Sound Processor, Cochlear is expanding its Connected Care solutions for Nucleus Implant System recipients. Building upon the ability to let cochlear implant recipients adjust their own processor settings and access Remote Care** options from their mobile phone, enhancements to the Nucleus Smart App will enable future improvements to the bimodal control experience and provide access to Remote Firmware updates, so patients can conveniently access the latest technology without a trip to the clinic. For those living with severe to profound sensorineural hearing loss, cochlear implants are a proven medical treatment option. Cochlear implants are the most appropriate option to treat hearing loss when it has reached the level of severe to profound. However, conservative estimates suggest that only 1 in 20 adults worldwide who could benefit from a cochlear implant has one.13,14 Better hearing can help people reach their full potential. The Nucleus 8 Sound Processor will be commercially available across the United States and Canada by the end of 2022. The Nucleus 8 Sound Processor has been approved by Health Canada. About Cochlear Limited (ASX: COH) People have always been Cochlear's inspiration, ever since Professor Graeme Clark set out to create the first multi-channel cochlear implant after seeing his father struggle with hearing loss. Since 1981, Cochlear has provided more than 700,000 devices in more than 180 countries, helping people of all ages around the world to hear. As the global leader in implantable hearing solutions, Cochlear connects people with life's opportunities, and welcomes them to the world's largest hearing implant community. Cochlear has a global workforce of more than 4,500 people, with a passion for progress, who strive to meet the needs of people living with hearing loss. The company continually innovates to anticipate future needs, investing more than AUD$2 billion to date in research and development to push the boundaries of technology and help more people hear. References [cited 2022 Feb 28]. Available from: [cited 2022 Feb 28]. Available from: [cited 2022 Feb 28]. Available from: Cochlear Limited D1864200 SCAN-X Design Description. Apr 2022. Mauger SJ, Warren C, Knight M, Goorevich M, Nel E. Clinical evaluation of the Nucleus 6 cochlear implant system: performance improvements with SmartSound iQ. International Journey Of Audiology. 2014, Aug; 53(8): 564-576. [Sponsored by Cochlear] Mauger S, Jones M, Nel E, Del Dot J. Clinical outcomes with the Kanso™ off- the-ear cochlear implant sound processor. International Journal Of Audiology. 2017, Jan 9; 1-10. [Sponsored by Cochlear] Wolfe J, Neumann S, Marsh M, Schafer E, Lianos L, Gilden J, O'Neill L, Arkis P, Menapace C, Nel E, Jones M. Benefits of Adaptive Signal Processing in a Commercially Available Cochlear Implant Sound Processor. Otol Neurotol. 2015 Aug;36(7):1181-90. [Sponsored by Cochlear] Cochlear Limited. D1964109 Clinical Investigation Report CLTD5804. Feb 2022. Cochlear Limited. D1190805, Processor Size Comparison. May 2022. Hunn N. Introducing Bluetooth® LE Audio [Internet]. [cited 2022 Jan]. Available from: . Cochlear Limited. D1631375 Nucleus 8 Sound Processor Product Definition. A Technical Overview of LC3 [Internet]. Bluetooth® Technology Website. [cited 2022 Feb 28]. Available from: . Sorkin D. Cochlear implantation in the world's largest medical device market: utilization and awareness of cochlear implants in the United States. Cochlear Implants Int 2013;14(Suppl 1):S1. De Raeve L. Cochlear implants in Belgium: Prevalence in paediatric and adult cochlear implantation. Eur Ann Otorhinolaryngol Head Neck Dis 2016;133(Suppl 1):S57–60. Disclaimers # When the technology becomes available for the Cochlear Nucleus 8 Sound Processor, a firmware update to your sound processor will allow you to connect to Bluetooth LE Audio compatible devices. * Compared to Nucleus 6 and 7 Sound Processors. + ForwardFocus can only be enabled by a hearing implant specialist. It should only be activated for users 12 years and older who are able to reliably provide feedback on sound quality and understand how to use the feature when moving to different or changing environments. It may be possible to have decreased speech understanding when using ForwardFocus in a quiet environment. Ù Compared to Nucleus® 7 Sound Processor with ForwardFocus on. ± Comparison made using the Compact Battery Module for Nucleus 8 Sound Processor and the Compact Rechargeable Battery for Nucleus 7 Sound Processor. ** Remote Check and Remote Assist are intended for ages 6 and older. Remote Check and Remote Assist features are only visible and accessible if they are enabled by a clinician. Clinicians should consider the suitability of the feature before enabling Remote Check and Remote Assist. The Bluetooth® and AuracastTM word mark and logos are registered trademarks owned by Bluetooth SIG, Inc., and any use of such marks by Cochlear Limited is under license. Please seek advice from your health professional about treatments for hearing loss. Outcomes may vary, and your health professional will advise you about the factors which could affect your outcome. Always follow the directions for use. Not all products are available in all countries. Please contact your local Cochlear representative for product information. © Cochlear Limited 2022. All rights reserved. SOURCE Cochlear Limited