The hexosamine biosynthetic pathway rescues lysosomal dysfunction in-vitro in Parkinson’s disease

- Posted by

Some people advocate for Parkinson's patients to consume mannitol. Many individuals affected by the disease began consuming daily oral mannitol. Self-reported outcomes included an improved sense of smell, a reduction in the dose of PD medications, and general improvement in well-being. A clinical trial was done at Hadassah Medical Center in Israel by David Arkadir and colleagues.

The lobby group CliniCrowd was probably instrumental in this decision.

The study lasted 36 weeks and included four dose escalations of oral mannitol (manufacturer Roquette, France) or dextrose as a placebo from 2.5 g to a maximal dose of 18 g per day. The COVID-19 pandemic in 2020 dramatically slowed the recruitment rate in the 3rd year of the clinical trial and led to the decision to earlier trial termination. They did not observe a clear reduction in Parkinson's symptoms. It is possible that a longer exposure would enable clinically to demonstrate disease modification. Anyway, such a high dose of mannitol is not without innuendoes, mannitol is hypertonic, it forces water to be excreted from cells. Yet the mechanism by which mannitol reduces α-synuclein accumulation in PD models was still unknown.

In 2022 another study showed that glycation agents (sugars) can ameliorate α-synuclein folding. Glycation is increased in the brains of hyperglycemic patients. Alpha-synuclein (αSN), a central player in the etiology of Parkinson’s disease, can be glycated so reducing αSN fibril formation. The best glycating agents were unfortunately toxic, but one agent was mildly efficacious while not toxic: Mannose.

Mannitol, while usually derived from fructose, can also be derived from a mannose by reduction. In the human body, mannose residues are used to assemble N-glycans by adding them to a dolichol phosphate (Dol-P) core in the Endoplasmic Reticulum (ER) of cells.

There's a growing body of research suggesting a connection between abnormal N-glycans and neurodegenerative diseases like Alzheimer's and Parkinson's. N-glycans are sugar chains attached to proteins in a specific way, and changes in their structure or abundance seem to play a role in these diseases. This means the sugar chains are either attached differently, have different structures, or are present in abnormal amounts.

N-glycans can influence how proteins fold, interact with other molecules, and get transported within cells. In a recent publication, scientists analyzed neurons in iPSC midbrain cultures derived from patients with Parkinson's disease and they discovered the disruption of a metabolic pathway, the hexosamine pathway. The hexosamine pathway is important for protein synthesis, transport, and folding in the neuron's endoplasmic reticulum. enter image description here The hexosamine pathway produces N-linked glycans, essential molecules that support protein folding in the endoplasmic reticulum.

The hexosamine pathway (a biological pathway is the way a molecule is created from components) uses glucose and uridine-5’-triphosphate to generate N-linked glycans for protein folding in the endoplasmic reticulum. In Parkinson's midbrain cultures, however, this N-glycosylation process was interrupted, causing protein misfolding and accumulation of α-synuclein.

Accelerating glucose flux through the hexosamine pathway rescued hydrolase function and reduced pathological α-synuclein.

So as a non-scientist, I can conclude this post by saying that there is some rationality in using mannitol in Parkinson's disease, while it might not be the silver bullet people are waiting for.

Please, help us continue to provide valuable information: