Development of targeted therapies for Parkinson's disease and related synucleinopathies
Therapeutic efforts in neurodegenerative diseases have been very challenging, particularly due to a lack of validated and mechanism-based therapeutic targets and biomarkers. The basic idea underlying the novel therapeutic approaches reviewed here is that by exploring the molecular basis of neurodege...
Main Authors: | , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2014-10-01
|
Series: | Journal of Lipid Research |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520350033 |
id |
doaj-4de44c7236f9493a9b36da7e8a17d03a |
---|---|
record_format |
Article |
spelling |
doaj-4de44c7236f9493a9b36da7e8a17d03a2021-04-28T05:58:53ZengElsevierJournal of Lipid Research0022-22752014-10-01551019962003Development of targeted therapies for Parkinson's disease and related synucleinopathiesEdmund Sybertz0Dimitri Krainc1Lysosomal Therapeutics, Inc., Boston, MA 02114To whom correspondence should be addressed; Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; To whom correspondence should be addressedTherapeutic efforts in neurodegenerative diseases have been very challenging, particularly due to a lack of validated and mechanism-based therapeutic targets and biomarkers. The basic idea underlying the novel therapeutic approaches reviewed here is that by exploring the molecular basis of neurodegeneration in a rare lysosomal disease such as Gaucher's disease (GD), new molecular targets will be identified for therapeutic development in common synucleinopathies. Accumulation of α-synuclein plays a key role in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies, suggesting that improved clearance of α-synuclein may be of therapeutic benefit. To achieve this goal, it is important to identify specific mechanisms and targets involved in the clearance of α-synuclein. Recent discovery of clinical, genetic, and pathological linkage between GD and PD offers a unique opportunity to examine lysosomal glucocerebrosidase, an enzyme mutated in GD, for development of targeted therapies in synucleinopathies. While modulation of glucocerebrosidase and glycolipid metabolism offers a viable approach to treating disorders associated with synuclein accumulation, the compounds described to date either lack the ability to penetrate the CNS or have off-target effects that may counteract or limit their capabilities to mediate the desired pharmacological action. However, recent emergence of selective inhibitors of glycosphingolipid biosynthesis and noninhibitory pharmacological chaperones of glycosphingolipid processing enzymes that gain access to the CNS provide a novel approach that may overcome some of the limitations of compounds reported to date. These new strategies may allow for development of targeted treatments for synucleinopathies that affect both children and adults.http://www.sciencedirect.com/science/article/pii/S0022227520350033glucocerebrosidaselysosomesglycosphingolipids |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Edmund Sybertz Dimitri Krainc |
spellingShingle |
Edmund Sybertz Dimitri Krainc Development of targeted therapies for Parkinson's disease and related synucleinopathies Journal of Lipid Research glucocerebrosidase lysosomes glycosphingolipids |
author_facet |
Edmund Sybertz Dimitri Krainc |
author_sort |
Edmund Sybertz |
title |
Development of targeted therapies for Parkinson's disease and related synucleinopathies |
title_short |
Development of targeted therapies for Parkinson's disease and related synucleinopathies |
title_full |
Development of targeted therapies for Parkinson's disease and related synucleinopathies |
title_fullStr |
Development of targeted therapies for Parkinson's disease and related synucleinopathies |
title_full_unstemmed |
Development of targeted therapies for Parkinson's disease and related synucleinopathies |
title_sort |
development of targeted therapies for parkinson's disease and related synucleinopathies |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2014-10-01 |
description |
Therapeutic efforts in neurodegenerative diseases have been very challenging, particularly due to a lack of validated and mechanism-based therapeutic targets and biomarkers. The basic idea underlying the novel therapeutic approaches reviewed here is that by exploring the molecular basis of neurodegeneration in a rare lysosomal disease such as Gaucher's disease (GD), new molecular targets will be identified for therapeutic development in common synucleinopathies. Accumulation of α-synuclein plays a key role in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies, suggesting that improved clearance of α-synuclein may be of therapeutic benefit. To achieve this goal, it is important to identify specific mechanisms and targets involved in the clearance of α-synuclein. Recent discovery of clinical, genetic, and pathological linkage between GD and PD offers a unique opportunity to examine lysosomal glucocerebrosidase, an enzyme mutated in GD, for development of targeted therapies in synucleinopathies. While modulation of glucocerebrosidase and glycolipid metabolism offers a viable approach to treating disorders associated with synuclein accumulation, the compounds described to date either lack the ability to penetrate the CNS or have off-target effects that may counteract or limit their capabilities to mediate the desired pharmacological action. However, recent emergence of selective inhibitors of glycosphingolipid biosynthesis and noninhibitory pharmacological chaperones of glycosphingolipid processing enzymes that gain access to the CNS provide a novel approach that may overcome some of the limitations of compounds reported to date. These new strategies may allow for development of targeted treatments for synucleinopathies that affect both children and adults. |
topic |
glucocerebrosidase lysosomes glycosphingolipids |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520350033 |
work_keys_str_mv |
AT edmundsybertz developmentoftargetedtherapiesforparkinsonsdiseaseandrelatedsynucleinopathies AT dimitrikrainc developmentoftargetedtherapiesforparkinsonsdiseaseandrelatedsynucleinopathies |
_version_ |
1721504697397805056 |