Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms
Cumulative evidence collected in recent decades suggests that lysosomal dysfunction contributes to neurodegenerative diseases, especially if amyloid proteins are involved. Among these, alpha-synuclein (aSyn) that progressively accumulates and aggregates in Lewy bodies is undisputedly a main culprit...
Main Authors: | , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2020-11-01
|
Series: | Frontiers in Cell and Developmental Biology |
Subjects: | |
Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2020.598446/full |
id |
doaj-7e43dc0e4925496c812d2e5c718fb29b |
---|---|
record_format |
Article |
spelling |
doaj-7e43dc0e4925496c812d2e5c718fb29b2020-11-25T03:08:30ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2020-11-01810.3389/fcell.2020.598446598446Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein ProteoformsNorelle C. Wildburger0Norelle C. Wildburger1Anna-Sophia Hartke2Alina Schidlitzki3Franziska Richter4Franziska Richter5Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hanover, GermanyCenter for Systems Neuroscience, Hanover, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hanover, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hanover, GermanyDepartment of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hanover, GermanyCenter for Systems Neuroscience, Hanover, GermanyCumulative evidence collected in recent decades suggests that lysosomal dysfunction contributes to neurodegenerative diseases, especially if amyloid proteins are involved. Among these, alpha-synuclein (aSyn) that progressively accumulates and aggregates in Lewy bodies is undisputedly a main culprit in Parkinson disease (PD) pathogenesis. Lysosomal dysfunction is evident in brains of PD patients, and mutations in lysosomal enzymes are a major risk factor of PD. At first glance, the role of protein-degrading lysosomes in a disease with pathological protein accumulation seems obvious and should guide the development of straightforward and rational therapeutic targets. However, our review demonstrates that the story is more complicated for aSyn. The protein can possess diverse posttranslational modifications, aggregate formations, and truncations, all of which contribute to a growing known set of proteoforms. These interfere directly or indirectly with lysosome function, reducing their own degradation, and thereby accelerating the protein aggregation and disease process. Conversely, unbalanced lysosomal enzymatic processes can produce truncated aSyn proteoforms that may be more toxic and prone to aggregation. This highlights the possibility of enhancing lysosomal function as a treatment for PD, if it can be confirmed that this approach effectively reduces harmful aSyn proteoforms and does not produce novel, toxic proteoforms.https://www.frontiersin.org/articles/10.3389/fcell.2020.598446/fullalpha-synucleinproteoformslysosomeParkinson diseaseGCase |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Norelle C. Wildburger Norelle C. Wildburger Anna-Sophia Hartke Alina Schidlitzki Franziska Richter Franziska Richter |
spellingShingle |
Norelle C. Wildburger Norelle C. Wildburger Anna-Sophia Hartke Alina Schidlitzki Franziska Richter Franziska Richter Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms Frontiers in Cell and Developmental Biology alpha-synuclein proteoforms lysosome Parkinson disease GCase |
author_facet |
Norelle C. Wildburger Norelle C. Wildburger Anna-Sophia Hartke Alina Schidlitzki Franziska Richter Franziska Richter |
author_sort |
Norelle C. Wildburger |
title |
Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms |
title_short |
Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms |
title_full |
Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms |
title_fullStr |
Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms |
title_full_unstemmed |
Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms |
title_sort |
current evidence for a bidirectional loop between the lysosome and alpha-synuclein proteoforms |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cell and Developmental Biology |
issn |
2296-634X |
publishDate |
2020-11-01 |
description |
Cumulative evidence collected in recent decades suggests that lysosomal dysfunction contributes to neurodegenerative diseases, especially if amyloid proteins are involved. Among these, alpha-synuclein (aSyn) that progressively accumulates and aggregates in Lewy bodies is undisputedly a main culprit in Parkinson disease (PD) pathogenesis. Lysosomal dysfunction is evident in brains of PD patients, and mutations in lysosomal enzymes are a major risk factor of PD. At first glance, the role of protein-degrading lysosomes in a disease with pathological protein accumulation seems obvious and should guide the development of straightforward and rational therapeutic targets. However, our review demonstrates that the story is more complicated for aSyn. The protein can possess diverse posttranslational modifications, aggregate formations, and truncations, all of which contribute to a growing known set of proteoforms. These interfere directly or indirectly with lysosome function, reducing their own degradation, and thereby accelerating the protein aggregation and disease process. Conversely, unbalanced lysosomal enzymatic processes can produce truncated aSyn proteoforms that may be more toxic and prone to aggregation. This highlights the possibility of enhancing lysosomal function as a treatment for PD, if it can be confirmed that this approach effectively reduces harmful aSyn proteoforms and does not produce novel, toxic proteoforms. |
topic |
alpha-synuclein proteoforms lysosome Parkinson disease GCase |
url |
https://www.frontiersin.org/articles/10.3389/fcell.2020.598446/full |
work_keys_str_mv |
AT norellecwildburger currentevidenceforabidirectionalloopbetweenthelysosomeandalphasynucleinproteoforms AT norellecwildburger currentevidenceforabidirectionalloopbetweenthelysosomeandalphasynucleinproteoforms AT annasophiahartke currentevidenceforabidirectionalloopbetweenthelysosomeandalphasynucleinproteoforms AT alinaschidlitzki currentevidenceforabidirectionalloopbetweenthelysosomeandalphasynucleinproteoforms AT franziskarichter currentevidenceforabidirectionalloopbetweenthelysosomeandalphasynucleinproteoforms AT franziskarichter currentevidenceforabidirectionalloopbetweenthelysosomeandalphasynucleinproteoforms |
_version_ |
1724665928892809216 |