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Brain, Jul 08 2024, awae222 | https://doi.org/10.1093/brain/awae222 Gba1 E326K renders motor and non-motor symptoms with pathologic α-syn, tau and glial activation

Sin Ho Kweon,^1,2,† Hye Guk Ryu,^3,† Seung-Hwan Kwon,^1,2 Hyeonwoo Park,³ Saebom Lee,^1,2,4, Nam-Shik Kim,^1,2Shi-Xun Ma,^1,2 Hee-Jung Jee,⁵ Sangjune Kim^3,‡ and Han Seok Ko^1,2,6,‡

¹Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

²Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

³Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea

⁴Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea

⁵Department of Information and Statistics, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea

⁶Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA

Correspondence to: Sangjune Kim, Han Seok Ko

^†,‡These authors contributed equally to this work.

Abstract

Mutations in the GBA1 gene are common genetic risk factors for Parkinson's disease (PD), disrupting enzymatic activity and causing lysosomal dysfunction, leading to elevated α-synuclein (α-syn) levels. While GBA1's role in synucleinopathy is well-established, recent research underscores neuroinflammation as a significant pathogenic mechanism in GBA1 deficiency. This study investigates neuroinflammation in Gba1 E326K knock-in mice, a model associated with increased PD and dementia risk. At 9 and 24 months, we assessed GBA1 protein and activity, α-synuclein pathology, neurodegeneration, motor deficits, and gliosis in the ventral midbrain and hippocampus using immunohistochemistry (IHC), Western blot (WB), and GCase assays. Additionally, primary microglia from WT and GBA1E326K/E326K mice were treated with α-syn preformed fibrils (PFF) to study microglia activation, pro-inflammatory cytokines, reactive astrocyte formation, and neuronal death through qPCR, WB, and immunocytochemistry analyses. We also evaluated the effects of gut inoculation of α-syn PFF in Gba1 E326K mice at 7 months and striatal inoculation at 10 months, assessing motor/non-motor symptoms, α-syn pathology, neuroinflammation, gliosis, and neurodegeneration via behavioural tests, IHC, and WB assays. At 24 months, Gba1 E326K knock-in mice showed reduced GCase enzymatic activity and glucosylceramide build-up in the ventral midbrain and hippocampus. Increased pro-inflammatory cytokines and reactive astrocytes were observed in microglia and astrocytes from Gba1 E326K mice treated with pathologic α-syn PFF. Gut inoculation of α-syn PFF increased Lewy body accumulation in the hippocampal dentate gyrus, with heightened microglia and astrocyte activation and worsened non-motor symptoms. Intrastriatal α-syn preformed fibril injection induced motor deficits, reactive glial protein accumulation, and tauopathy in the prefrontal cortex and hippocampus of Gba1 E326K mice. GBA1 deficiency due to the Gba1 E326K mutation exacerbates neuroinflammation and promotes pathogenic α-synuclein transmission, intensifying disease pathology in PD models. This study enhances our understanding of how the Gba1 E326K mutation contributes to neuroinflammation and the spread of pathogenic α-syn in the brain, suggesting new therapeutic strategies for PD and related synucleinopathies.

논문정보

형식Research article
게재일2024년 07월 (BRIC 등록일 2024-07-10)
연구진국내(교신)+국외 연구진
분야 생명과학 > 신경생물학

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