Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease
Abstract Missense variants in leucine-rich repeat kinase 2 (LRRK2) lead to familial and sporadic Parkinson’s disease (PD). The pathological features of PD patients with LRRK2 variants differ. Here, we report an autopsy case harboring the LRRK2 G2385R, a risk variant for PD occurring mainly in Asian...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-08-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-022-00367-y |
| _version_ | 1797642340079239168 |
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| author | Toshiki Tezuka Daisuke Taniguchi Mariko Sano Tomoyo Shimada Yutaka Oji Taiji Tsunemi Aya Ikeda Yuanzhe Li Hiroyo Yoshino Jun Ogata Kahori Shiba-Fukushima Manabu Funayama Kenya Nishioka Yuzuru Imai Nobutaka Hattori |
| author_facet | Toshiki Tezuka Daisuke Taniguchi Mariko Sano Tomoyo Shimada Yutaka Oji Taiji Tsunemi Aya Ikeda Yuanzhe Li Hiroyo Yoshino Jun Ogata Kahori Shiba-Fukushima Manabu Funayama Kenya Nishioka Yuzuru Imai Nobutaka Hattori |
| author_sort | Toshiki Tezuka |
| collection | DOAJ |
| description | Abstract Missense variants in leucine-rich repeat kinase 2 (LRRK2) lead to familial and sporadic Parkinson’s disease (PD). The pathological features of PD patients with LRRK2 variants differ. Here, we report an autopsy case harboring the LRRK2 G2385R, a risk variant for PD occurring mainly in Asian populations. The patient exhibited levodopa-responsive parkinsonism at the early stage and visual hallucinations at the advanced stage. The pathological study revealed diffuse Lewy bodies with neurofibrillary tangles, amyloid plaques, and mild signs of neuroinflammation. Biochemically, detergent-insoluble phospho-α-synuclein was accumulated in the frontal, temporal, entorhinal cortexes, and putamen, consistent with the pathological observations. Elevated phosphorylation of Rab10, a substrate of LRRK2, was also prominent in various brain regions. In conclusion, G2385R appears to increase LRRK2 kinase activity in the human brain, inducing a deleterious brain environment that causes Lewy body pathology. |
| first_indexed | 2024-03-11T13:58:39Z |
| format | Article |
| id | doaj.art-f5424e9f60a54fa681ba5d764347fb97 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-11T13:58:39Z |
| publishDate | 2022-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-f5424e9f60a54fa681ba5d764347fb972023-11-02T05:43:41ZengNature Portfolionpj Parkinson's Disease2373-80572022-08-01811710.1038/s41531-022-00367-yPathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s diseaseToshiki Tezuka0Daisuke Taniguchi1Mariko Sano2Tomoyo Shimada3Yutaka Oji4Taiji Tsunemi5Aya Ikeda6Yuanzhe Li7Hiroyo Yoshino8Jun Ogata9Kahori Shiba-Fukushima10Manabu Funayama11Kenya Nishioka12Yuzuru Imai13Nobutaka Hattori14Department of Neurology, Juntendo University School of MedicineDepartment of Neurology, Juntendo University School of MedicineDepartment of Neurology, Juntendo University School of MedicineDepartment of Neurology, Juntendo University School of MedicineDepartment of Neurology, Juntendo University School of MedicineDepartment of Neurology, Juntendo University School of MedicineDepartment of Neurology, Juntendo University School of MedicineDepartment of Neurology, Juntendo University School of MedicineResearch Institute for Diseases of Old Age, Juntendo University Graduate School of MedicineDepartment of Research for Parkinson’s Disease, Juntendo University Graduate School of MedicineDepartment of Drug Development for Parkinson’s Disease, Juntendo University Graduate School of MedicineDepartment of Neurology, Juntendo University School of MedicineDepartment of Neurology, Juntendo University School of MedicineDepartment of Neurology, Juntendo University School of MedicineDepartment of Neurology, Juntendo University School of MedicineAbstract Missense variants in leucine-rich repeat kinase 2 (LRRK2) lead to familial and sporadic Parkinson’s disease (PD). The pathological features of PD patients with LRRK2 variants differ. Here, we report an autopsy case harboring the LRRK2 G2385R, a risk variant for PD occurring mainly in Asian populations. The patient exhibited levodopa-responsive parkinsonism at the early stage and visual hallucinations at the advanced stage. The pathological study revealed diffuse Lewy bodies with neurofibrillary tangles, amyloid plaques, and mild signs of neuroinflammation. Biochemically, detergent-insoluble phospho-α-synuclein was accumulated in the frontal, temporal, entorhinal cortexes, and putamen, consistent with the pathological observations. Elevated phosphorylation of Rab10, a substrate of LRRK2, was also prominent in various brain regions. In conclusion, G2385R appears to increase LRRK2 kinase activity in the human brain, inducing a deleterious brain environment that causes Lewy body pathology.https://doi.org/10.1038/s41531-022-00367-y |
| spellingShingle | Toshiki Tezuka Daisuke Taniguchi Mariko Sano Tomoyo Shimada Yutaka Oji Taiji Tsunemi Aya Ikeda Yuanzhe Li Hiroyo Yoshino Jun Ogata Kahori Shiba-Fukushima Manabu Funayama Kenya Nishioka Yuzuru Imai Nobutaka Hattori Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease npj Parkinson's Disease |
| title | Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease |
| title_full | Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease |
| title_fullStr | Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease |
| title_full_unstemmed | Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease |
| title_short | Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease |
| title_sort | pathophysiological evaluation of the lrrk2 g2385r risk variant for parkinson s disease |
| url | https://doi.org/10.1038/s41531-022-00367-y |
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