Neurological disorders of the microbiome-gut-brain axis

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative disorders characterized by a progressive degeneration of the central nervous system. Aggregates of the tau and α-synuclein (α-syn) proteins are major hallmarks of these diseases, respectively, and likely involved in their etiologies. In addition, these proteins are the key culprits in various other tauopathies and synucleinopathies. The tau protein gradually forms neurofibrillary tangles inside neurons causing the disintegration of cytoskeletal structure and neuronal death that eventually results in severe cognitive, memory, and functional impairments in AD. Similar to AD, PD is triggered by insoluble α-syn-derived inclusions, known as Lewy bodies, that selectively destruct dopaminergic neurons in the substantial nigra. PD patients with the loss of dopaminergic neurons suffer from movement related symptoms including tremor, rigidity, bradykinesia, as well as autonomic dysfunction and neuropsychiatric problems in later stages. In addition to these insoluble entities, soluble forms of tau and α-syn aggregates are also likely involved in the cell type specific neurotoxicity seen in these diseases. Notably, the pathogenesis of PD in particular and possibly AD have been proposed to initiate largely in the gastrointestinal tract of these patients where tau and α-syn aggregates may originate and spread to the brain through the gut-brain axis such as vagal nerves. Importantly, there are no effective therapies approved for targeting and eliminating tau or α-synuclein aggregates or cures for these diseases by other means.

Our laboratory recently embarked on a study to understand the pathophysiology of these neurological diseases that were initiated in the gut possibly through the injurious interactions with gut microbiome and investigate the mechanisms by which Lewy bodies (and neurofibrillary tangles) spread to the brain through the gut-brain axis using the rodent and Drosophila models.