A naturally occurring variant of SHLP2 is a protective factor in Parkinson’s disease
Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) have been associated with a reduced risk of developing Parkinson’s disease (PD), yet the underlying mechanisms remain elusive. In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived...
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| Veröffentlicht in: | Molecular psychiatry 2024-02, Vol.29 (2), p.505-517 |
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| creator | Kim, Su-Jeong Miller, Brendan Hartel, Nicolas G. Ramirez, Ricardo Braniff, Regina Gonzalez Leelaprachakul, Naphada Huang, Amy Wang, Yuzhu Arpawong, Thalida Em Crimmins, Eileen M. Wang, Penglong Sun, Xianbang Liu, Chunyu Levy, Daniel Yen, Kelvin Petzinger, Giselle M. Graham, Nicholas A. Jakowec, Michael W. Cohen, Pinchas |
| description | Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) have been associated with a reduced risk of developing Parkinson’s disease (PD), yet the underlying mechanisms remain elusive. In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD. |
| doi_str_mv | 10.1038/s41380-023-02344-0 |
| format | Article |
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In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD.</description><identifier>ISSN: 1359-4184</identifier><identifier>ISSN: 1476-5578</identifier><identifier>EISSN: 1476-5578</identifier><identifier>DOI: 10.1038/s41380-023-02344-0</identifier><identifier>PMID: 38167865</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/109 ; 14 ; 14/63 ; 38/109 ; 38/77 ; 42 ; 45 ; 631/378 ; 631/80 ; 82 ; 82/1 ; 82/58 ; Animals ; Behavioral Sciences ; Biological Psychology ; Disease Models, Animal ; DNA, Mitochondrial - genetics ; Electron Transport Complex I - genetics ; Electron Transport Complex I - metabolism ; Humanin ; Humans ; Intracellular Signaling Peptides and Proteins ; Male ; Mass spectroscopy ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred C57BL ; Mitochondria - metabolism ; Mitochondrial DNA ; Mitochondrial Proteins - genetics ; Mitochondrial Proteins - metabolism ; Movement disorders ; Neurodegenerative diseases ; Neurons - metabolism ; Neurosciences ; Parkinson Disease - genetics ; Parkinson Disease - metabolism ; Parkinson's disease ; Peptides ; Peptides - genetics ; Peptides - metabolism ; Pharmacotherapy ; Polymorphism, Single Nucleotide - genetics ; Protective Factors ; Psychiatry ; Single-nucleotide polymorphism</subject><ispartof>Molecular psychiatry, 2024-02, Vol.29 (2), p.505-517</ispartof><rights>The Author(s) 2023</rights><rights>2023. The Author(s).</rights><rights>The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD.</description><subject>13</subject><subject>13/109</subject><subject>14</subject><subject>14/63</subject><subject>38/109</subject><subject>38/77</subject><subject>42</subject><subject>45</subject><subject>631/378</subject><subject>631/80</subject><subject>82</subject><subject>82/1</subject><subject>82/58</subject><subject>Animals</subject><subject>Behavioral Sciences</subject><subject>Biological Psychology</subject><subject>Disease Models, Animal</subject><subject>DNA, Mitochondrial - genetics</subject><subject>Electron Transport Complex I - genetics</subject><subject>Electron Transport Complex I - metabolism</subject><subject>Humanin</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Male</subject><subject>Mass spectroscopy</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondrial DNA</subject><subject>Mitochondrial Proteins - genetics</subject><subject>Mitochondrial Proteins - metabolism</subject><subject>Movement disorders</subject><subject>Neurodegenerative diseases</subject><subject>Neurons - metabolism</subject><subject>Neurosciences</subject><subject>Parkinson Disease - genetics</subject><subject>Parkinson Disease - metabolism</subject><subject>Parkinson's disease</subject><subject>Peptides</subject><subject>Peptides - genetics</subject><subject>Peptides - metabolism</subject><subject>Pharmacotherapy</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Protective Factors</subject><subject>Psychiatry</subject><subject>Single-nucleotide polymorphism</subject><issn>1359-4184</issn><issn>1476-5578</issn><issn>1476-5578</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNp9kMtKxTAQhoMo3l_AhQTcuKlObm2yFPEGBxS8bENOOpVoT3tMWsGdr-Hr-SS2Hi_gwkWYwHzzz_ARssPggIHQh0kyoSEDLsYnZQZLZJ3JIs-UKvTy8BfKZJJpuUY2UnoAGJtqlawJzfJC52qd3B3RxnV9dHX9Qlvv-xhDc0-fXQyu6Whb0evzyRWnIVFH57Ht0HfhGWnlfNdGGhp65eJjaFLbvL--JVqGhC7hFlmpXJ1w-6tuktvTk5vj82xyeXZxfDTJvGSmywRwrqalL1FhZfKyyrGQBRimzFRx7aXOnSlYIVSpEUyFGkvmBBgvvGNCiE2yv8gdTnvqMXV2FpLHunYNtn2y3DBgBrgZ0b0_6EPbx2a4zgpQhrGCgxoovqB8bFOKWNl5DDMXXywDO1q3C-t2MG4_rVsYhna_ovvpDMufkW_NAyAWQJqPejH-7v4n9gMnToyS</recordid><startdate>20240201</startdate><enddate>20240201</enddate><creator>Kim, Su-Jeong</creator><creator>Miller, Brendan</creator><creator>Hartel, Nicolas G.</creator><creator>Ramirez, Ricardo</creator><creator>Braniff, Regina Gonzalez</creator><creator>Leelaprachakul, Naphada</creator><creator>Huang, Amy</creator><creator>Wang, Yuzhu</creator><creator>Arpawong, Thalida Em</creator><creator>Crimmins, Eileen M.</creator><creator>Wang, Penglong</creator><creator>Sun, Xianbang</creator><creator>Liu, Chunyu</creator><creator>Levy, Daniel</creator><creator>Yen, Kelvin</creator><creator>Petzinger, Giselle M.</creator><creator>Graham, Nicholas A.</creator><creator>Jakowec, Michael W.</creator><creator>Cohen, Pinchas</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7890-2395</orcidid><orcidid>https://orcid.org/0000-0002-4435-5757</orcidid><orcidid>https://orcid.org/0000-0003-4595-971X</orcidid><orcidid>https://orcid.org/0000-0001-9671-9535</orcidid><orcidid>https://orcid.org/0009-0006-8219-7311</orcidid><orcidid>https://orcid.org/0000-0002-6811-1941</orcidid><orcidid>https://orcid.org/0000-0003-1843-8724</orcidid><orcidid>https://orcid.org/0000-0002-7461-7973</orcidid><orcidid>https://orcid.org/0000-0002-2929-2807</orcidid><orcidid>https://orcid.org/0000-0001-6191-9975</orcidid><orcidid>https://orcid.org/0000-0002-0035-8366</orcidid></search><sort><creationdate>20240201</creationdate><title>A naturally occurring variant of SHLP2 is a protective factor in Parkinson’s disease</title><author>Kim, Su-Jeong ; 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In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>38167865</pmid><doi>10.1038/s41380-023-02344-0</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-7890-2395</orcidid><orcidid>https://orcid.org/0000-0002-4435-5757</orcidid><orcidid>https://orcid.org/0000-0003-4595-971X</orcidid><orcidid>https://orcid.org/0000-0001-9671-9535</orcidid><orcidid>https://orcid.org/0009-0006-8219-7311</orcidid><orcidid>https://orcid.org/0000-0002-6811-1941</orcidid><orcidid>https://orcid.org/0000-0003-1843-8724</orcidid><orcidid>https://orcid.org/0000-0002-7461-7973</orcidid><orcidid>https://orcid.org/0000-0002-2929-2807</orcidid><orcidid>https://orcid.org/0000-0001-6191-9975</orcidid><orcidid>https://orcid.org/0000-0002-0035-8366</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/109 14 14/63 38/109 38/77 42 45 631/378 631/80 82 82/1 82/58 Animals Behavioral Sciences Biological Psychology Disease Models, Animal DNA, Mitochondrial - genetics Electron Transport Complex I - genetics Electron Transport Complex I - metabolism Humanin Humans Intracellular Signaling Peptides and Proteins Male Mass spectroscopy Medicine Medicine & Public Health Mice Mice, Inbred C57BL Mitochondria - metabolism Mitochondrial DNA Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Movement disorders Neurodegenerative diseases Neurons - metabolism Neurosciences Parkinson Disease - genetics Parkinson Disease - metabolism Parkinson's disease Peptides Peptides - genetics Peptides - metabolism Pharmacotherapy Polymorphism, Single Nucleotide - genetics Protective Factors Psychiatry Single-nucleotide polymorphism |
| title | A naturally occurring variant of SHLP2 is a protective factor in Parkinson’s disease |
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