| Autor: |
Yang Q; Department of Neurobiology, Neurology and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing Institute of Geriatrics, Beijing, China.; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China., Pang S; Department of Neurobiology, Neurology and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing Institute of Geriatrics, Beijing, China., Zhao C; Department of Neurobiology, Neurology and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing Institute of Geriatrics, Beijing, China., Wang Y; Department of Neurobiology, Neurology and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing Institute of Geriatrics, Beijing, China., Lu J; Department of Neurobiology, Neurology and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing Institute of Geriatrics, Beijing, China.; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China., Yue Z; Department of Neurobiology, Icahn School of Medicine at Mount Sinai, New York, USA., Chan P; Department of Neurobiology, Neurology and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing Institute of Geriatrics, Beijing, China.; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China.; Clinical Center for Parkinson's Disease, Capital Medical University, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory for Parkinson's Disease, Beijing, China.; Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China. |
| Abstrakt: |
Leucine-rich repeat kinase 2 (LRRK2)-R1628P mutation has been shown to be one of the common risk factors for Parkinson's disease (PD) in Asian populations, but the mechanism by which R1628P mutations cause neuronal dysfunction remains unknown. We used LRRK2 R1627P knock-in rats (human LRRK2-R1628P corresponds to rat LRRK2-R1627P) to investigate the R1627P mutation on function of dopaminergic neurons (DANs) and their susceptibility to the environmental toxin Lipopolysaccharide (LPS) during aging. LRRK2 R1627P rats showed no significant loss of DANs, dopamine and its metabolites, or motor dysfunction; however, spontaneous exploration and olfactory discrimination reduced, and dendritic spines of DANs showed degeneration. We found decreased p Thr73 -Rab10 located on the trans-Golgi, disrupted Golgi structure and lipofuscin accumulation in aged LRRK2 R1627P rat DANs, and the protein related to trans-Golgi complex and regulating lysosome function were significantly reduced. Although the neuroinflammation of brain was not obvious in the aging process, we confirmed a decrease in the ratio of CD4 + /CD8 + and B cells, an increase in inflammatory factors (TLR4, NFKB, TNF-α) in the periphery. Furthermore, we demonstrated that the R1627P mutation caused the abnormal accumulation of α-Syn in the aged rat intestine. LPS exacerbated pathological α-Syn aggregation in the small intestine of LRRK2 transgenic rats and spread to the brain via the gut-brain axis. This led to microgliosis in the substantia nigra, creating a pro-inflammatory environment and inducing DANs degeneration. Gut-brain axis disruption may be a key determinant of progression to R1628P-PD in R1628P carriers. This insight has important clinical implications and highlights the importance of monitoring and addressing gut-brain axis integrity in individuals with LRRK2 mutations. |
