Mutations in the GBA1 gene are one of the most common genetic risk factors associated with Parkinson's disease (PD). However, it's important to note that not all people with GBA1 mutations will necessarily develop PD. Furthermore, if they do, the onset may occur at different ages and with different clinical presentations. This variability highlights the critical need to identify additional factors, both environmental and genetic, that may influence the likelihood of developing PD in individuals with GBA1 mutations.

Individuals with GBA1-related PD often have a higher prevalence of non-motor symptoms, such as a reduced sense of smell and constipation, which typically precede the onset of motor symptoms. The characteristic tremors, rigidity, slowness of movement, and freezing in PD have been attributed to the loss of certain brain cells called dopaminergic neurons, along with the accumulation of a protein called α-synuclein in the brain. Interestingly, a hypothesis emerged in 2003 that the initial pathology of α-synuclein may originate in the gastrointestinal tract before progressing to the brain. Specifically, people with PD often have alterations in their gut microbiota, resulting in changes in the maintenance of the intestinal lining, inflammation, and the body's ability to defend itself against invading pathogens.

Of particular interest are short-chain fatty acids, which have potential anti-inflammatory and neuroprotective properties. These compounds are produced by certain types of gut bacteria through the fermentation of dietary fiber. They do not only provide energy to gut cells but also support the regeneration and maintenance of optimal intestinal barrier function. However, it remains unknown whether alterations in short-chain fatty acids and other microbial molecules influence the likelihood of GBA1 mutations leading to PD.

Supported by the US initiative Aligning Science Across Parkinson's (ASAP), our research laboratory is investigating how GBA1 mutations might interact with microbial molecules to promote inflammation and α-synuclein accumulation using various cell culture systems. So far, we've obtained skin biopsies from PD patients with the E326K or L444P mutations, two GBA1 variants commonly associated with PD. We reprogrammed the skin cells to create induced pluripotent stem cells (iPSCs), which have the potential to become any type of cell. We first differentiated iPSCs into two different types of immune cells - peripheral macrophages and microglia found in the brain - to compare how GBA1 mutations affect immune cell function in the peripheral and central nervous systems.

Both types of immune cells exhibited reduced GBA1 activity. Interestingly, brain-dwelling microglia carrying the L444P GBA1 mutation showed an increase in cytokine secretion associated with the recruitment of peripheral immune cells. Building on this work, we analyzed intestinal organoids derived from GBA1-related PD patients. These organoids are three-dimensional structures that mimic the cellular composition and behaviour of the human gastrointestinal tract. We discovered that reduced GBA1 activity correlates with an increased presence of α-synuclein, suggesting that our model system accurately reflects changes observed in PD patients.

In an effort to more accurately mimic the complexity of the human gastrointestinal tract and to study the spread of α-synuclein from the gut to the brain, we are currently developing gut-brain chip models. The gut-on-chip model incorporates intestinal organoids and vascular cells with mechanical forces to mimic real physiological conditions. This system will allow us to study the role of GBA1 and short-chain fatty acids in maintaining the intestinal barrier, identify the molecular mechanisms involved in α-synuclein accumulation, and assess the potential recruitment of immune cells from blood vessels into the tissue. We will then investigate whether manipulating the microbiome, balancing inflammation, or restoring GBA1 function could reduce the risk, delay the onset, or slow the progression of PD in individuals with GBA1 mutations. The results of this research have the potential to pave the way for personalized medicine tailored to this genetically distinct patient population.

Christin Weissleder, PhD works at the Imagine Institute of Genetic Diseases (Paris, France). She was a Hot Topic presenter at the WPC 2023 in Barcelona on “Uncovering the interaction between gut microbial factors and GBA1 mutations in the pathogenesis of Parkinson's disease.“
Twitter: @c_weissleder

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