Parkinson’s Disease and Taste: Comparison
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In the common language, the word “taste” is often used to describe sensations arising from the oral cavity. However, in biology the sense of taste includes all sensations mediated by a chemosensory gustatory system specialized anatomically and physiologically. The molecular mechanisms underlying the perception of taste include the reception and signal transduction mechanisms, which play important roles in the oral cavity and also in a diversity of tissues including the respiratory and gastrointestinal tracts, kidney and even brain.

  • Parkinson’s disease
  • taste

1. Taste System

Taste sensation begins with the activation of taste receptor cells (TRCs), which are organized in taste buds located mostly on the superior surface of the tongue. The reception and transduction mechanisms of taste stimuli are located at the chemosensory apical tip of the TRCs. The generated signals are transmitted, via three cranial nerves (CN) (facial, VII; glossopharyngeal, IX and vagus, X), to the rostral part of the solitary tract nucleus (NST) of the medulla. The projections from the NST include parabrachial nucleus, thalamus (ventral posteromedial nucleus), gustatory areas of the cortex in the insula, amygdala, hypothalamus and basal ganglia

[1]

.

It is generally assumed that human taste sensations can be divided into five qualities: bitter, sour, salty, sweet, and umami. Recently, the fat taste has been acknowledged as a sixth primary sensory quality

[2][3][4][5]

.

2. Chemoreceptors, Receptor Genes and Taste

Chemoreceptors of the plasma membrane of TRCs interact with specific chemical stimuli to initiate an afferent signal to the brain, which results in taste perception. Specialized chemoreceptors mediate specific coding mechanisms for different taste stimuli and provide the basis for discrimination across taste qualities

[6]

. In humans, the chemoreception of sweet, umami, and bitter taste involves membrane proteins from the TAS1R and TAS2R families, which belong to a superfamily of G protein–coupled receptors (GPCRs). Various receptors for detection of long chain fatty acids have been proposed

[7][8]

, including CD36

[4][9][10]

. Candidate chemoreceptors have been suggested for salty and sour taste qualities

[11][12][13][14][15]

. The existence of several chemoreceptors reflect the importance of distinguishing beneficial from harmful chemicals of the environment

[16]

.

Progress with understanding of the interaction between taste stimuli and chemoreceptors and the identifying of patterns of their expression in taste cells sheds light on coding of taste information by the nervous system

[17]

. Variations in taste receptor genes affect expression and function of taste receptors, and therefore influence taste function

[18]

. It is well known that variation in taste receptor genes can result in differences of the sweet, umami and bitter perception, while less is known about the genetics of sour and salty taste

[19]

. The 

TAS2R38

 gene, codifying for receptor binding the bitter-tasting thiourea compounds such as PROP and PTC, is one of the most studied in this field

[20]

. Variations in 

TAS2R38

 gene greatly contribute to the thiourea taster groups: super-tasters, medium tasters and non-tasters

[21][22]

.

3. Extra-Gustatory Taste Receptors

As stated above, taste receptors and signal transduction molecules for sweet, bitter, and umami tastes are expressed not only in TRCs of oral cavity, but also in cells of a variety of extra-oral tissues throughout the body, including the brain

[23]

. The functions of this internal chemoreceptors have only been partially elucidated. However, it possible to state that they detect chemical compounds of internal environment and that modifications of this internal chemo-sensation can affect physiological functions

[24]

. Specifically, TAS2Rs, which detect bitter compounds, mediate several non-tasting functions and their genetic variants are associated with diverse disorders

[25]

. Brain neurons have been shown to respond to different chemicals

[26]

. Bitter TAS2Rs are expressed in multiple regions of the rat brain, TAS2R4, TAS2R107 and TAS2R38 are expressed in the brain stem, cerebellum, cortex, and nucleus accumbens and calcium signaling showed the functionality of T2R4 expressed in these cells

[27]

.

4. Taste Dysfunction in Neurogenerative Disease (Overview)

Taste dysfunctions are described as ageusia (complete loss of taste), hypogeusia (partial loss of taste), parageusia (inadequate or wrong taste perception) and phantogeusia (presence of a persistent and unpleasant taste)

[28]

. Taste disorders are generally associated to medical conditions, pharmacologic or surgical interventions, exposure to toxic chemicals, head injury, advanced age or neurodegenerative diseases

[29][30][31][32][33][34][35][36][37][38]

. Over recent years, the link between taste dysfunctions and neurodegenerative disorders has increasingly been recognized. Some authors showed patients with Alzheimer’s disease (AD) to reporte significant reduction of taste function, by showing an increase of the detection threshold of the four basic tastes (sweet, salty, sour, and bitter)

[33][34]

. However, others reported no difference in detection threshold of sucrose

[39][40]

and sour

[39]

or total absence of taste alterations

[41]

. In a case study, Petzold et al.

[42]

indicated that patients with amyotrophic lateral sclerosis (ALS) reported a persistent bitter or metallic taste (phantogeusia), although no hypogeusia for taste qualities were observed. Tarlarini and colleagues showed reduction of taste and its negative consequences on psychological status and quality of life in ALS patients

[43]

. Taste disorders also have been described as a prominent early feature in Creutzfeldt–Jakob disease (CJD) which is one of prion diseases, a group of neurodegenerative disorders, characterized by accumulation of abnormal prion proteins in the central nervous system. In 2001, Reuber and colleagues describe for the first time a patient with CJD whose first symptoms included deficits of taste and smell

[44]

.

5. Taste Impairments in PD

In recent years several studies evaluated gustatory function in PD patients

[29][30][31][45][46][47][48]

, but reporting inconsistent results. This may because they were carried out by using small sample size or different assessment methods: whole mouth test (WMT), supra-threshold taste solutions sprayed into the oral cavity

[49]

; taste strip test, (TST), in which patients had to identify a taste from a taste strip

[50][51]

and electrogustometry (EGM), rapid measure of taste threshold by using electric current as stimulus)

[52][53]

.

Despite the different tests adopted by the research groups, it is generally reported that taste can be affected in PD patients by showing persistent, but slight and stable taste impairments

[54]

. In particular, most of the studies identified a reduced taste sensitivity with an estimated frequency between 9% and 27%

[29][30][31][32]

. Shah et al.

[31]

, using EGM, found that about 27% of PD patients had an impaired taste function. Taste thresholds measured in the front and back of the tongue were higher in PD patients, than in healthy controls (HC), suggesting significant deficits in CN VII and CN IX. Deeb et al.

[30]

by using EGM showed that about 22% of PD patients had impaired taste function. Kim et al.

[29]

by using TSTs reported a decrease in the ability to identify tastants in female but not in male PD patients when compared to HC. Cecchini et al.

[48]

reported difference between PD patients and HC in taste performance assessed by the TST, but not by WMT. In fact, only the TST score was significantly lower in PD patients than HC. The reason of the fact that WMT do not show reduction of taste could be due to the use of stimuli at supra-threshold concentration, which are not able to capture slight impairment of taste function.

Doty et al.

[55]

studied whole-mouth (WMT) and regional taste perception of early-stage PD patients and HC matched on the basis of age, sex, and race. They reported that the WMT scores were lower in the PD patients than in controls (for all four taste stimuli), and the intensity ratings for the weaker concentrations of all stimuli, except caffeine, tended to be higher in the PD patients than in HC. This last finding is consistent with the findings of Sienkiewicz- Jarosz and co-workers who demonstrated that, in the WMT test, PD patients rated quinine

[45]

and sucrose as more intense than HC

[46]

. Moreover, Doty et al.

[55]

using regional tests showed that subjects tended to better identify and rate the stimuli as more intense on the front than in the back of the tongue with respect to controls. These findings suggest that the suprathreshold measures of taste function are influenced by PD which differentially influences taste function on CN VII and CN IX. These results are not observed if the taste techniques are limited to WM. In addition, in the same study

[55]

EGM was not able to observe differences between the PD patients and controls. In addition, a reduced identification of sweet

[56]

, salty or bitter stimuli was found

[55]

. Despite the slightly controversial results, it appears that taste is affected in PD, although less frequently than smell. However, future investigations are necessary to explore the causes of taste impairments related to PD.

It is interesting to note that the taste loss has been related mostly to the advanced stages of the disease

[30]

, whereas reports on prodromal presentation are rare. Pont-Sunyer and colleagues

[57]

observed that the time of the taste loss onset varied between 2 and 10 years before diagnosis. Taste loss was present before the onset of motor symptoms in more than 70% of PD patients, providing evidence for a very-early onset of taste loss, which is comparable to that of olfactory impairments. Therefore, the evaluation of the taste function may be used in combination with that olfactory as a potential marker of PD. However, it is known that anosmics are more poorly able to taste than normal persons

[58][59][60]

.

6. Role of Taste Receptors in PD

The role of taste and smell receptors in PD has been investigated showing that the cortical olfactory receptors (ORs) and the TAS2Rs are altered in PD patients

[61]

. Olfactory receptors OR2L13, OR1E1, OR2J3, OR52L1, and OR11H1 and taste receptors TAS2R5 and TAS2R50 were downregulated, whereas TAS2R10 and TAS2R13 were upregulated, at premotor and parkinsonian stages, in the frontal cortex area 8 of the brains in PD patients

[61]

. These findings support the idea that ORs and TA2SRs in the cerebral cortex may have physiologic functions that are affected in PD patients. The identification of altered regulation of OR and TAS2R in PD patients, suggests the study of the chemical signaling system of the brain to understand the mechanisms involved in the occurrence of the neurodegenerative diseases. Future studies will have to point out whether the altered TAS2R may play a role in the inflammatory mechanisms associated with the initiation of misfolding of the α-synuclein cascade.

7. Relationships between TAS2R38 and Taste Dysfunction in PD

TAS2R38 has been associated with a variety of non-tasting physiological mechanisms

[62][20][25][63][64][65][66][67]

. The allelic diversity of the gene codifying for TAS2R38 results in three non-synonymous coding single nucleotide polymorphisms (SNPs), which give rise to two major variants: the functional form containing proline, alanine and valine (haplotype named PAV) and the non-functional variant containing alanine, valine and isoleucine (haplotype named AVI)

[22][68]

. TAS2R38 SNPs dictate individual differences in PTC/PROP tasting

[22][69][70]

, food linking patterns

[64][71]

and also in TAS2R38‒mediated pathophysiology

[25]

, such as susceptibility, severity, and prognosis of upper respiratory infection, rhinosinusitis and biofilm formation in chronic rhinosinusitis patients

[72][73][74][75][76][77][78][79]

, development of colonic neoplasm

[80][81][82]

, taste disorders

[83]

, and neurodegenerative diseases

[84]

.

In the following paragraphs, we focus on TAS2R38 polymorphisms, the relative ability to perceive the bitter taste of thiourea compounds and its association with microbiota, as a genetic risk factors for development of PD.

Moberg and colleagues were the first that examine PTC sensitivity in PD patients and HC to determine whether taster status can be a marker for PD. They showed significant differences in the distribution of taster and non-taster subjects between the PD patients HC. They showed that only 44% of PD patients could detect the bitterness of PTC, as compared to 75% of HC

[85]

. Cossu et al.

[84]

confirmed the result showing a reduced of PROP taste sensitivity in PD patients compared to HC. Specifically, a decreased perceived taste intensity and reduced ability to recognize bitter-taste quality was found. They also showed an increase in the frequency of the PD patients classified as PROP non-tasters (54.13%) and a decrease in frequency of PD patients classified as PROP super-tasters (8.25%) compared to HC. Furthermore, the results showed that the homozygous genotype for the tasting variant of TAS2R38 (PAV) was uncommon in PD patients, only 5% of them carried this genotype, whereas most of them carried the non-taster form (AVI). These results seem to indicate that individuals who have a couple of tasting haplotypes (PAV/PAV) at TAS2R38 may be at lower risk of developing PD, with respect to those with the haplotype (AVI). Therefore, the latter might represent a prodromal genetic marker for the identification of early pre-degenerative changes that could be instrumental to understand the origin of this disorder. Thus, studying the PROP phenotype and genotype may represent a new, simple way to identify increased predisposition for PD.

8. Role of Microbiota on Relationships between TAS2R38 and Taste Dysfunction in PD

PD has been associated with the dysbiosis of gut microbiota

[86]

and imbalance in gut microbiota plays an important role in worsening of disease

[87][88][89][90]

. Specific taste receptors, expressed in the lower gastrointestinal tract (GI), respond to change of the composition of gut microbiota and regulate immune responses against pathogens

[25][91][92][93]

. In particular, it is known that when TAS2R38 expressed in the enteroendocrine cells of the gut is activated by bacterial molecules, it increases the release of β-defensin (an anti-microbial compound)

[25]

and a peptide hormone termed cholecystokinin (CCK). This hormone can limit the absorption of dietary toxins

[94][95]

, inhibit feeding behavior and gastric function

[96][97][98]

and it also can play a key role in regulating the immune response to antigens and bacterial toxins

[99]

. Thus, the response of TAS2R38 represents an important defense of the organism in contrasting the noxious effects in the gut lumen.

Vascellari et al.

[100]

showed that the composition of the gut microbiota was different across genotypes of TAS2R38 in PD patients. Specifically, a decrease in bacteria alpha-diversity with a predominant reduction of 

Clostridium

 genus was associated with AVI/AVI genotype, compared to the PAV/PAV genotype. It is important to mention that some members of 

Clostridium

 genus produce toxin

[101]

, while other members confer beneficial effects which has a multitude of metabolic function in the GI tract, such as modulation of gastrointestinal motility, barrier integrity and immune response

[101][102][103]

. Therefore, a decrease in the abundance of helpful-

Clostridium

 molecules associated to a high frequency of the form of TAS2R38 receptor at a low affinity for the ligands might determine, in PD, a decrease in the activation of protective signaling-molecules involved in the regulation of the immune response. This factor could affect different cellular processes which are impaired in PD, thereby contributing to the development of gut dysbiosis

[100]

.

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