Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases
Lysosomal acidification dysfunction has been implicated as a key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Multiple genetic factors have been linked to lysosomal de-acidification through impairing the vacuolar-t...
| Main Authors: | , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2023
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/169231 |
| _version_ | 1826125719034396672 |
|---|---|
| author | Lo, Chih Hung Zeng, Jialiu |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Lo, Chih Hung Zeng, Jialiu |
| author_sort | Lo, Chih Hung |
| collection | NTU |
| description | Lysosomal acidification dysfunction has been implicated as a key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Multiple genetic factors have been linked to lysosomal de-acidification through impairing the vacuolar-type ATPase and ion channels on the organelle membrane. Similar lysosomal abnormalities are also present in sporadic forms of neurodegeneration, although the underlying pathogenic mechanisms are unclear and remain to be investigated. Importantly, recent studies have revealed early occurrence of lysosomal acidification impairment before the onset of neurodegeneration and late-stage pathology. However, there is a lack of methods for organelle pH monitoring in vivo and a dearth of lysosome-acidifying therapeutic agents. Here, we summarize and present evidence for the notion of defective lysosomal acidification as an early indicator of neurodegeneration and urge the critical need for technological advancement in developing tools for lysosomal pH monitoring and detection both in vivo and for clinical applications. We further discuss current preclinical pharmacological agents that modulate lysosomal acidification, including small molecules and nanomedicine, and their potential clinical translation into lysosome-targeting therapies. Both timely detection of lysosomal dysfunction and development of therapeutics that restore lysosomal function represent paradigm shifts in targeting neurodegenerative diseases. |
| first_indexed | 2024-10-01T06:40:56Z |
| format | Journal Article |
| id | ntu-10356/169231 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:40:56Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1692312023-07-16T15:37:41Z Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases Lo, Chih Hung Zeng, Jialiu Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Neurodegenerative Diseases Alzheimer’s Disease Lysosomal acidification dysfunction has been implicated as a key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Multiple genetic factors have been linked to lysosomal de-acidification through impairing the vacuolar-type ATPase and ion channels on the organelle membrane. Similar lysosomal abnormalities are also present in sporadic forms of neurodegeneration, although the underlying pathogenic mechanisms are unclear and remain to be investigated. Importantly, recent studies have revealed early occurrence of lysosomal acidification impairment before the onset of neurodegeneration and late-stage pathology. However, there is a lack of methods for organelle pH monitoring in vivo and a dearth of lysosome-acidifying therapeutic agents. Here, we summarize and present evidence for the notion of defective lysosomal acidification as an early indicator of neurodegeneration and urge the critical need for technological advancement in developing tools for lysosomal pH monitoring and detection both in vivo and for clinical applications. We further discuss current preclinical pharmacological agents that modulate lysosomal acidification, including small molecules and nanomedicine, and their potential clinical translation into lysosome-targeting therapies. Both timely detection of lysosomal dysfunction and development of therapeutics that restore lysosomal function represent paradigm shifts in targeting neurodegenerative diseases. Nanyang Technological University National Medical Research Council (NMRC) Published version C.H.L. is supported by a Lee Kong Chian School of Medicine Dean’s Postdoctoral Fellowship (021207-00001) from Nanyang Technological University (NTU) Singapore and a Mistletoe Research Fellowship (022522-00001) from the Momental Foundation USA. J.Z. is supported by a Presidential Postdoctoral Fellowship (021229-00001) from NTU Singapore and an Open Fund Young Investigator Research Grant (OF-YIRG) (MOH-001147) from the National Medical Research Council (NMRC) Singapore. 2023-07-10T02:29:12Z 2023-07-10T02:29:12Z 2023 Journal Article Lo, C. H. & Zeng, J. (2023). Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases. Translational Neurodegeneration, 12(1), 29-. https://dx.doi.org/10.1186/s40035-023-00362-0 2047-9158 https://hdl.handle.net/10356/169231 10.1186/s40035-023-00362-0 37287072 2-s2.0-85161026827 1 12 29 en 021207-00001 021229-00001 MOH-001147 Translational Neurodegeneration © The Author(s) 2023. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. application/pdf |
| spellingShingle | Science::Medicine Neurodegenerative Diseases Alzheimer’s Disease Lo, Chih Hung Zeng, Jialiu Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases |
| title | Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases |
| title_full | Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases |
| title_fullStr | Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases |
| title_full_unstemmed | Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases |
| title_short | Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases |
| title_sort | defective lysosomal acidification a new prognostic marker and therapeutic target for neurodegenerative diseases |
| topic | Science::Medicine Neurodegenerative Diseases Alzheimer’s Disease |
| url | https://hdl.handle.net/10356/169231 |
| work_keys_str_mv | AT lochihhung defectivelysosomalacidificationanewprognosticmarkerandtherapeutictargetforneurodegenerativediseases AT zengjialiu defectivelysosomalacidificationanewprognosticmarkerandtherapeutictargetforneurodegenerativediseases |