Oral administration of Proteus mirabilis mutilates the dendritic morphology of striatal dopaminergic neurons leading to cognitive dysfunction
Description
Parkinson’s disease (PD) is an age-related disorder now the most common neurodegenerative disorder after Alzheimer’s disease which is identified by the motor symptoms occurring due to abnormalities in cortical region. A distinguished feature of the progressive loss of dopaminergic neurons in the basal ganglia region of the brain leads to motor and non-motor symptoms. The potential that gut microbial dysbiosis is linked to PD pathogenesis is indicated by prior research on pathological alterations in the intestines of PD patients and PD animal models. This study aims to target the gut bacteria that could be involved in the degeneration of striatal dopaminergic neurons and consequently progressing the symptoms of PD. The study explores the effect of Proteus in causing cognitive and behavioral changes in animal models and it further goes to the neuronal level to investigate how it affects the structural profile of striatal dopaminergic neurons. This study provides compelling evidence that intestinal colonization by *Proteus mirabilis* can trigger Parkinson’s disease (PD)-like neuropathological features in mice. Using a combination of fecal cultures, behavioral assays, histological analyses, and molecular techniques, the authors demonstrated a strong association between gut infection and neurodegeneration. Mice orally administered *P. mirabilis* exhibited significant bacterial colonization in feces, confirming successful gut infection. Behavioral testing revealed marked impairments in motor coordination and cognitive functions, resembling clinical symptoms of PD. Histopathological evaluation through Golgi-Cox staining and Sholl analysis revealed pronounced dendritic degeneration and reduced arborization in medium spiny neurons of the striatum, indicating synaptic dysfunction. Furthermore, immunofluorescence staining showed enhanced accumulation of α-synuclein aggregates in both the colon and various brain regions (notably the substantia nigra and striatum), consistent with Braak’s hypothesis that misfolded α-synuclein may propagate from the gut to the brain via the vagus nerve. Molecular analysis supported these pathological findings, showing decreased expression of tyrosine hydroxylase (TH), a marker for dopaminergic neurons, suggesting significant dopaminergic cell loss. Additionally, elevated levels of glial fibrillary acidic protein (GFAP) pointed to astroglial activation and neuroinflammation. Notably, these PD-like changes were similar to those seen in rotenone-induced models, a well-established toxin-based model of PD. Together, the findings support the notion that gut microbiota, specifically *P. mirabilis*, may play a causal role in PD by initiating synucleinopathy, neuroinflammation, and dopaminergic neurodegeneration. This highlights a novel potential mechanism in PD pathogenesis and suggests the gut-brain axis as a promising therapeutic target.
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Institutions
- Banaras Hindu University Institute of Medical Sciences