Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP.
Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause late-onset Parkinson's disease, but its physiological function has remained largely unknown. Here we report that LRRK2 activates a calcium-dependent protein kinase kinase-β (CaMKK-β)/adenosine monophosphate (AMP)-activated protein...
| Главные авторы: | , , , , , , , , |
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| Формат: | Journal article |
| Язык: | English |
| Опубликовано: |
2012
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| _version_ | 1826266479597715456 |
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| author | Gómez-Suaga, P Luzón-Toro, B Churamani, D Zhang, L Bloor-Young, D Patel, S Woodman, P Churchill, G Hilfiker, S |
| author_facet | Gómez-Suaga, P Luzón-Toro, B Churamani, D Zhang, L Bloor-Young, D Patel, S Woodman, P Churchill, G Hilfiker, S |
| author_sort | Gómez-Suaga, P |
| collection | OXFORD |
| description | Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause late-onset Parkinson's disease, but its physiological function has remained largely unknown. Here we report that LRRK2 activates a calcium-dependent protein kinase kinase-β (CaMKK-β)/adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway which is followed by a persistent increase in autophagosome formation. Simultaneously, LRKR2 overexpression increases the levels of the autophagy receptor p62 in a protein synthesis-dependent manner, and decreases the number of acidic lysosomes. The LRRK2-mediated effects result in increased sensitivity of cells to stressors associated with abnormal protein degradation. These effects can be mimicked by the lysosomal Ca(2+)-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) and can be reverted by an NAADP receptor antagonist or expression of dominant-negative receptor constructs. Collectively, our data indicate a molecular mechanism for LRRK2 deregulation of autophagy and reveal previously unidentified therapeutic targets. |
| first_indexed | 2024-03-06T20:39:35Z |
| format | Journal article |
| id | oxford-uuid:33d0bdbd-c2a2-439a-95e9-f052023be01d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:39:35Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:33d0bdbd-c2a2-439a-95e9-f052023be01d2022-03-26T13:22:25ZLeucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:33d0bdbd-c2a2-439a-95e9-f052023be01dEnglishSymplectic Elements at Oxford2012Gómez-Suaga, PLuzón-Toro, BChuramani, DZhang, LBloor-Young, DPatel, SWoodman, PChurchill, GHilfiker, SMutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause late-onset Parkinson's disease, but its physiological function has remained largely unknown. Here we report that LRRK2 activates a calcium-dependent protein kinase kinase-β (CaMKK-β)/adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway which is followed by a persistent increase in autophagosome formation. Simultaneously, LRKR2 overexpression increases the levels of the autophagy receptor p62 in a protein synthesis-dependent manner, and decreases the number of acidic lysosomes. The LRRK2-mediated effects result in increased sensitivity of cells to stressors associated with abnormal protein degradation. These effects can be mimicked by the lysosomal Ca(2+)-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) and can be reverted by an NAADP receptor antagonist or expression of dominant-negative receptor constructs. Collectively, our data indicate a molecular mechanism for LRRK2 deregulation of autophagy and reveal previously unidentified therapeutic targets. |
| spellingShingle | Gómez-Suaga, P Luzón-Toro, B Churamani, D Zhang, L Bloor-Young, D Patel, S Woodman, P Churchill, G Hilfiker, S Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. |
| title | Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. |
| title_full | Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. |
| title_fullStr | Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. |
| title_full_unstemmed | Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. |
| title_short | Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. |
| title_sort | leucine rich repeat kinase 2 regulates autophagy through a calcium dependent pathway involving naadp |
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