Therapeutic Potential of αS Evolvability for NeuropathicGaucher Disease
Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, <i>GBA1</i>. In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and sev...
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doaj-a14a9b2544544c2ebbcc73814e73afb32021-02-16T00:03:20ZengMDPI AGBiomolecules2218-273X2021-02-011128928910.3390/biom11020289Therapeutic Potential of αS Evolvability for NeuropathicGaucher DiseaseJianshe Wei0Yoshiki Takamatsu1Ryoko Wada2Masayo Fujita3Gilbert Ho4Eliezer Masliah5Makoto Hashimoto6Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, JapanTokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, JapanTokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, JapanTokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, JapanPCND Neuroscience Research Institute, Poway, CA 92064, USADivision of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USATokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, JapanGaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, <i>GBA1</i>. In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and severer neuropathic forms with early onset (GD2/3). Currently, no radical therapies are established for GD2/3. Notably, GD1, but not GD2/3, is associated with increased risk of Parkinson’s disease (PD)<i>, the </i>elucidation of which might provide a clue for novel therapeutic strategies. In this context, the objective of the present study is to discuss that the evolvability of α-synuclein (αS) might be differentially involved in GD subtypes. Hypothetically, aging-associated PD features with accumulation of αS, and the autophagy-lysosomal dysfunction might be an antagonistic pleiotropy phenomenon derived from αS evolvability in the development in GD1, without which neuropathies like GD2/3 might be manifested due to the autophagy-lysosomal dysfunction. Supposing that the increased severity of GD2/3 might be attributed to the decreased activity of αS evolvability, suppressing the expression of β-synuclein (βS), a potential buffer against αS evolvability, might be therapeutically efficient. Of interest, a similar view might be applicable to Niemann-Pick type C (NPC), another LSD, given that the adult type of NPC, which is comorbid with Alzheimer’s disease, exhibits milder medical symptoms compared with those of infantile NPC. Thus, it is predicted that the evolvability of amyloid β and tau, might be beneficial for the adult type of NPC. Collectively, a better understanding of amyloidogenic evolvability in the pathogenesis of LSD may inform rational therapy development.https://www.mdpi.com/2218-273X/11/2/289Gaucher disease (GD), Parkinson’s disease (PD), autosomal recessiveα-synuclein (αS), evolvabilityantagonistic pleiotropyβ-synuclein (βS) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jianshe Wei Yoshiki Takamatsu Ryoko Wada Masayo Fujita Gilbert Ho Eliezer Masliah Makoto Hashimoto |
spellingShingle |
Jianshe Wei Yoshiki Takamatsu Ryoko Wada Masayo Fujita Gilbert Ho Eliezer Masliah Makoto Hashimoto Therapeutic Potential of αS Evolvability for NeuropathicGaucher Disease Biomolecules Gaucher disease (GD), Parkinson’s disease (PD), autosomal recessive α-synuclein (αS), evolvability antagonistic pleiotropy β-synuclein (βS) |
author_facet |
Jianshe Wei Yoshiki Takamatsu Ryoko Wada Masayo Fujita Gilbert Ho Eliezer Masliah Makoto Hashimoto |
author_sort |
Jianshe Wei |
title |
Therapeutic Potential of αS Evolvability for NeuropathicGaucher Disease |
title_short |
Therapeutic Potential of αS Evolvability for NeuropathicGaucher Disease |
title_full |
Therapeutic Potential of αS Evolvability for NeuropathicGaucher Disease |
title_fullStr |
Therapeutic Potential of αS Evolvability for NeuropathicGaucher Disease |
title_full_unstemmed |
Therapeutic Potential of αS Evolvability for NeuropathicGaucher Disease |
title_sort |
therapeutic potential of αs evolvability for neuropathicgaucher disease |
publisher |
MDPI AG |
series |
Biomolecules |
issn |
2218-273X |
publishDate |
2021-02-01 |
description |
Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, <i>GBA1</i>. In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and severer neuropathic forms with early onset (GD2/3). Currently, no radical therapies are established for GD2/3. Notably, GD1, but not GD2/3, is associated with increased risk of Parkinson’s disease (PD)<i>, the </i>elucidation of which might provide a clue for novel therapeutic strategies. In this context, the objective of the present study is to discuss that the evolvability of α-synuclein (αS) might be differentially involved in GD subtypes. Hypothetically, aging-associated PD features with accumulation of αS, and the autophagy-lysosomal dysfunction might be an antagonistic pleiotropy phenomenon derived from αS evolvability in the development in GD1, without which neuropathies like GD2/3 might be manifested due to the autophagy-lysosomal dysfunction. Supposing that the increased severity of GD2/3 might be attributed to the decreased activity of αS evolvability, suppressing the expression of β-synuclein (βS), a potential buffer against αS evolvability, might be therapeutically efficient. Of interest, a similar view might be applicable to Niemann-Pick type C (NPC), another LSD, given that the adult type of NPC, which is comorbid with Alzheimer’s disease, exhibits milder medical symptoms compared with those of infantile NPC. Thus, it is predicted that the evolvability of amyloid β and tau, might be beneficial for the adult type of NPC. Collectively, a better understanding of amyloidogenic evolvability in the pathogenesis of LSD may inform rational therapy development. |
topic |
Gaucher disease (GD), Parkinson’s disease (PD), autosomal recessive α-synuclein (αS), evolvability antagonistic pleiotropy β-synuclein (βS) |
url |
https://www.mdpi.com/2218-273X/11/2/289 |
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