Sex-dependent interactions between prodromal intestinal inflammation and LRRK2 G2019S in mice promote endophenotypes of Parkinson's disease.
Commun Biol
; 7(1): 570, 2024 May 15.
Article
en En
| MEDLINE
| ID: mdl-38750146
ABSTRACT
Gastrointestinal (GI) disruptions and inflammatory bowel disease (IBD) are commonly associated with Parkinson's disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD endophenotypes in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male mice promotes α-synuclein aggregation in the substantia nigra, loss of dopaminergic neurons and motor impairment. This male bias is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by increases in α-synuclein in the colon, α-synuclein-positive macrophages in the colonic lamina propria, and loads of phosphorylated α-synuclein within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD endophenotypes in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of α-synuclein in myeloid cells within the gut.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Enfermedad de Parkinson
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Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Año:
2024
Tipo del documento:
Article