Johns Hopkins Medicine researchers say they have added evidence that the farnesol compound, which occurs naturally in herbs, berries and other fruits, prevents and reverses Parkinson’s brain damage in mouse studies. The compound, used in flavorings and perfume making, can prevent the loss of dopamine-producing neurons in the brains of mice by deactivating PARIS, a key protein involved in disease progression. The loss of these neurons affects movement and cognition, leading to symptoms characteristic of Parkinson’s disease such as tremors, muscle stiffness, confusion and dementia. In the brains of people with Parkinson’s disease, a buildup of PARIS slows the production of the protective protein PGC-1alpha. This protein is a transcription factor that regulates the energy and formation of mitochondria. In a way, it protects brain cells from harmful reactive oxygen species that accumulate due to metabolism. Without PGC-1alpha, dopamine neurons degenerate and die, leading to the cognitive and physical changes associated with Parkinson’s disease.
The results of the new study, detail how researchers identified the potential of farnesol by examining an extensive drug library to find those that inhibit PARIS. For their intrinsic potential impact, the results have published in the journal Science Translational Medicine. To investigate whether farnesol could protect the brain from the effects of PARIS buildup, the researchers fed the mice either a farnesol-supplemented diet or a regular mouse diet for one week. Then, the researchers administered preformed fibrils of the protein alpha-synuclein, which is associated with the effects of Parkinson’s in the brain. Researchers found that mice fed the farnesol diet performed better in a strength and coordination test designed to detect the progression of parkinsonian symptoms. On average, mice performed 100% better than mice. injected with alpha-synuclein, but fed a regular diet. When the researchers subsequently studied the brain tissue of the mice in the two groups, they found that mice fed a farnesol-supplemented diet had twice as many healthy dopamine neurons as mice fed a simple diet.
Mice fed farnesol also had about 55% more protective PGC-1alpha protein in their brains than untreated mice. In chemical experiments, the researchers confirmed that farnesol covalently binds to PARIS, changing the shape of the protein so that it can no longer interfere with PGC-1alpha production. This modification is driven by enzymes (farnesylation) which also modify GTP-dependent proteins (G proteins) coupled to many types of membrane receptors. Among these are also dopamine receptors. Although less PARIS farnesylation is known to be present in the neurons of individuals with Parkinson’s disease, there is no scientific data that also supports the lack of G protein farnesylation in Parkinson’s. However, it is known that other non-receptor G proteins are farnesylated and are important for the prevention of cell death induced by oxidative stress, such as the K-Ras and Rac-1 proteins. Efficient farnesylation of these G proteins could prevent stress-induced degeneration of dopaminergic neurons, but these possibilities have not been investigated in this research.
It is not the first time, however that a fatty molecule seems to affect alpha-synuclein, the main protein under investigation implicated in Parkinson’s disease onset. In 2017, researchers led by professor Zasloff at the Georgetown University School of Medicine, demonstrated that show that squalamine, a natural product isolated from the dogfish shark, dramatically affects α-synuclein aggregation in vitro and in vivo. This fatty molecule is a precursor of cholesterol and it has been shown to suppress alpha-synulcein aggregates almost completely. Originally, squalamine has been found to have pharmacological activity in endothelial cells by inhibiting growth factor-dependent pathways, therefore representing a drug candidate for the treatment of cancer and macular degeneration. In their research, scientists studied squalamine for its ability to enter eukaryotic cells and displace proteins that are bound to the cytoplasmic face of plasma membranes. After this discovery, scientists shofted interest on the most novel knowledge about alpha-synuclein for the onset of parkinsonism: the axonal transportation that would make the disease rise from the gut.
Indeed, more recently another research team demonstrated that squalamine interferes with the aggregation of a mutatìnt form of alpha-synuclein (A53T) in the gut of a genetically engineered mouse. The study was corroborated by electrophysiology data showing that mutant protein impairs the natural gut motility, while administration of squalamine restores bowel motility and fecal expulsion in mice. The effects indeed is exerted on local neural cells. This molecular phenomenon is important and reflects a pivotal symptom of Parkinson’s disease that appears even years before the actual clinical symptomatology: chronic constipation. Impaired intestinal motility sooner or later leads to the subversion of the composition of the intestinal bacterial flora or microbiota. This would lead to a further neurochemical alteration that could be responsible for the emergence of one of the behavioral cornerstones of Parkinson’s: depression. The shift in composition towards a microbiota that produces more biogenic amines and aromatic compounds, rather than organic acids (Gram-positive fermentation), could allow the transfer of these substances to the central nervous system and negatively affect brain chemistry.
At the end of 2020, scientists have proven that a lesser production of organic acids by gut microbiota is a possible handmark for parkinsonism. Aromatic substances derived from food aminoacids include scatole, indole, indoleacetic acid, tiramine and other phenols. These may interfere with the dopaminergic network in the brain ultimately contributing to the depressive component of the disease. And the connection between alpha-synuclein and microbiota has been demonstrated, as has the role of an altered microbiota in the etiology of Parkinson’s. Yet not everyone who develops intestinal dysbiosis will develop parkinsonian syndrome; it is more likely, however, that they will undergo behavioral alterations in the spectrum of anxious or depressive syndromes. Therefore, in order for this intestinal mechanism to lead to Parkinson’s there must be an underlying genetic component, which includes mutations of various kinds in at least one offending protein, such as alpha-synuclein, Parkin, PARIS and so on. The fact that natural hydrophobic molecules interfere with the pathological functions of diseased proteins, bodes well that they can be used to restore certain biological and biochemical functions altered in this disease.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Jo A et al. Sci Transl Med. 2021; 13(604):eaax8891
Limbocker R et al. Front Neurosci. 2021; 15:680026.
Wang Q, Luo Y et al. Brain. 2021 Apr 15:awab156.
González-Sanmiguel J et al. Cells. 2020; 9(11):2476.
West CL et al. J Parkinsons Dis 2020; 10(4):1477-91.
Perni M et al. PNAS USA. 2017; 114(6):E1009-E1017.
Dott. Gianfrancesco Cormaci
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