ABSTRACT
Parkinson's disease is a progressive and degenerative disorder that results from the degeneration of dopaminergic neurons. This study includes age-related neurodegeneration such as PD. As the human lifespan is undeniably increasing, there is an increase in the constant threat of being affected by age-related diseases like PD, Alzheimer's, etc.
According to recent studies, it has been reported that calorie restriction has a salient role in modulating age in living organisms. They have implemented a series of experiments to find proof that PD, is an age-related disease, might get modulated by implementing calorie restriction on model organism Caenorhabditis elegans. This review summarizes research on the effect of calorie restriction on PD and major advances in the field of biomarkers for the discovery of diagnosis and progression of PD, with emphasis on neuroimaging.
INTRODUCTION
Parkinson's disease is an age-related progressive neurodegenerative movement disorder. It is characterized by irreversible degeneration of dopaminergic neurons in the Substantia Nigra, which results in the reduction of neurotransmitter dopamine (DA). Dopamine is responsible for a variety of functions in the body, that involves the transfer of messages to plan and coordinate body movements, memory, pleasurable rewards, good sleep, concentration, learning, cognition, behavior, etc. ' PD is the second most severe debilitating age-related disorder after Alzheimer's disease (AD) with an average onset age of about 60 years' [1]. PD can be caused due to a variety of reasons:
- (i) Uncontrolled death of dopaminergic neurons. As the action of dopamine is suppressed by another neurotransmitter called acetylcholine. Hence, imbalance in Acetylcholine and Dopamine levels may drive disease progression.
- (ii) Genes: Several genetic factors have indicated the increase of risk for a person developing Parkinson's disease (PD), also exactly how these make some people more susceptible to the condition is unclear. Parkinson's disease can also run in families, as a result of faulty genes being passed on to a child by their parents, but it's quite rare. 'Genetic basis of the disease involves a mutation in 6 genes viz. SNCA, LRRK2, PRKN, DJ1, PINK1 and ATP13A2' [1].
- (iii) Environmental risk factors: This is a broad spectrum to find the cause for PD. It can also be caused due to traumatic brain injury that results in the alteration in the level of consciousness, it has been associated with increased risk of developing PD but still, the reason is unclear. People coming in contact with hazardous pesticides and herbicides are also a risk of developing PD. The use of antipsychotics drugs such as Promazine, haloperidol, perphenazine, chlorpromazine, etc. for the treatment of a bipolar disorder, schizophrenia, and various other psychological disorders. They have the potential to cause PD and EPS (Extrapyramidal Side Effects).
- (iv) Age: It is the largest risk factor for developing PD. About 1% of people over 60 get PD. Also, it is found that PD is more common in males than in females [2].
- (v) Presence of Lewy bodies: it is the abnormal aggregation of a protein called alpha-synuclein, which gets developed inside the neuron. The reason behind the deposition is still not known.
PD has a variety of symptoms, which can derive from person to person as does the rate of progression. These symptoms can differentiate between movement symptoms and non-movement symptoms. Movement symptoms include bradykinesia (slowness of movement), dizziness or fainting, drooling, dyskinesia, dystonia, facial masking, postural instability, rigidity, stooped posture, tremor, trouble moving or walking. Non-movement symptoms include anxiety, apathy, breathing, and respiratory difficulties, cognitive changes, constipation and nausea, dementia, depression, fatigue, hallucinations/delusions, loss of smell, pain, sleep disorders, writing, speech and swallowing problem.
The patients are provided with symptomatic treatment, as there is no cure to PD, to date. Patients are being provided with symptomatic treatment in the form of dopamine agonist drugs like Levodopa, initially, it shows better results but after prolonged usage of this drug, patients stop responding to these drugs [1].
In these situations, diagnosis becomes a major factor in the treatment. The diagnosis of PD in patients is now mainly focused on clinical manifestations. Now, it is also found that PD shares many common clinical features with some other neurodegenerative diseases such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Synucleinopathies multiple system atrophy (MSA), dementia with Lewy bodies (DLB), etc. [2]. Hence, there are more chances for misdiagnosis of PD, since there are no sensitive and specific biomarkers validated to differentiate PD from other movement disorders concerning overlapping clinical symptoms. There is a need for an ideal biomarker that should meet the following requirements: high sensitivity and specificity with clinical validation, inexpensive, retest reproducibility, easy accessibility, and can easily monitor disease progression without being biased by age.
OBJECTIVES & REVIEW OF LITERATURE
The objective of the research is to study Sir-2.1 modulates calorie restriction to prevent Parkinson's disease. They employed a transgenic Caenorhabditis elegans model, to study the role of calorie restriction to reduce the effects of dopaminergic specific toxicity. C.elegans exhibit immense advantages in terms of studying neurodegenerative diseases [1]. As it is transparent and genetically assessable and can be made transgenic to express human alpha-synuclein [1]. It was found that sirtuins have an extensively related effect on calorie reduction. Sirtuins are the family of proteins that regulate cellular homeostasis. It functions only in the presence of NAD+. The basic role of sirtuins is to remove acetyl groups from other proteins by deacetylation. Sirtuins were found across the species, as it's conserved with evolution. Hence it is said that genes that are conserved have universal functions in many or all species. It was found that SIR-2 as a gene promotes longevity in yeast. Hence, various researches are required to analyze their effect on humans. They treated the worms with 6-hydroxy dopamine (6-OHDA), hydroxylated dopamine, a potent neurodegenerative agent, used in labs to mimic PD in various model organisms. In this experiment, C. elegans were treated with 6- hydroxy dopamine (6-OHDA) to achieve selective degeneration of dopaminergic neurons. Several methods of calorie restrictions (CR) have been used, most widely used is the availability of the minimum amount of E.Coli. After 48 hours the treatment was terminated by washing the worms. The analyses were carried out by observing the worms under a laser scanning confocal microscope. Fluorescence intensity was quantified using Image J software [1]. Then the observations were analyzed to frame a result. Estimation of dopamine has been conducted to check the effects of 6-OHDA on dopaminergic neurons. Hence, a quantitative test has been performed to check the levels of dopamine in the exposed elegans by using HPLC (High-performance liquid chromatography) and electrochemical detector. [1]
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RESEARCH GAPS & METHODS TO ADDRESS THE GAPS
Next-generation sequencing (NGS) is a great revolution in the field of biological sciences. It is also known as massively parallel sequencing technology. This technique has many advantages such as high accuracy, high sensitivity to detect low-frequency variants, ability to sequence hundreds - thousands of genes or gene regions simultaneously. We can also find the genes that contribute to Parkinson's disease, as it seems to be a very complex genetic disease, might be many genes interacting to cause this disease. We have studied that all the mutations do not have a direct effect on any individual. It's still vague that what are the exact variations in genes that contribute to Parkinson's disease. We can test if a mutation possessing effects by observing the proteins it codes and its involvement in PD. We can also try to perform semi-quantitative and real-time PCR which can detect exon arrangements, deletions, or insertions.
We can also involve the study proteomics, metabolomics, and transcriptomics in our research as it is a powerful tool which is capable of performing mass analyses to detect small changes in RNA profile in fluid and tissue, metabolites, and protein. We can also try to focus on the development and validation of biomarkers, as there is an urgent need for a perfect biomarker that can have a great impact on diagnosis and treatment. Our new research should be a combination of clinical, genetic, imaging, and laboratory data.
MAIN FINDINGS
The findings from this experiment is calorie restriction provided protection against 6-OHDA. It was observed that worms that are raised on the reduced-calorie diet exhibited a protective effect in dopaminergic neurons exhibiting an enhanced and complete expression of green fluorescence protein [1]. It is observed that worms that have been treated with 6-OHDA, indicated a consequential reduction of fluorescence intensity compared to that of untreated worms. There have been many studies that prove that excessive calorie intake can pose an increased risk of acquiring age-related diseases and metabolic disorders. Over-nutrition has detrimental effects on physical and mental health. It can gradually increase oxidative stress, brain inflammation, and insulin and leptin resistance. Therefore, individuals with low- calorie intake are at low risk of acquiring PD. According to the paper, it is observed that calorie restriction enhanced dopamine levels in worms treated with 6-OHDA. This treatment helps in bettering the dopaminergic neurophysiology, not only by preventing DA neurodegeneration but also increases the content of neurotransmitter dopamine.
It is also observed that calorie restriction mediated protection is SIR-2.1 dependent. SIR-2 orthologs (sirtuins) can be found in organisms from yeast to humans. It's an NAD+ dependent protein that deacetylates the histone that promotes transcriptional silencing. To study the role of SIR-2.1 in the aging process, they employed RNAi method to silence the SIR-2.1 in control, calorie-restricted, 6-OHDA treated, and 6-OHDA + calorie-restricted conditions. It was observed that SIR-2.1 has an important role in mediating the protective effect of calorie restriction on dopaminergic neurodegeneration.
CONCLUSION
The present findings also suggest that SIR-2.1 plays an important role in mediating the protective effect of calorie restriction on dopaminergic neurodegeneration. Summarizing the paper, it can be said that individuals who are more involved in physical activities such as exercise, yoga, cycling, walking, dancing, etc, and also follow low-calorie and low-fat diets are expected to be at reduced risk of acquiring Parkinson's disease. This shows an opportunity to develop therapeutic treatment in the future.
FUTURE PERSPECTIVES
In the current field of Parkinson's disease, scientists and doctors are working together to find a treatment or a prevention technique for PD. There are huge numbers of research conducted every year in this field, seeking to understand more about this disease and its susceptibility to develop in someone. Scientists are studying genetic, environmental, and age-related factors that can increase the chance of diagnosis and treatment. Scientists are studying and developing neuroprotective therapies that can help prevent symptoms from getting worse and stop the development of the disease. Scientists have not found any cure for PD till now, slow its progression and reverse the damage. Gene therapy has the potential to do all three.
There is the need to integrate molecular imaging technique with biomarkers at will improve the diagnostic accuracy of PD, even at the prodromal stage, as it's believed that neurodegenerative processes start several years before the inception of the movement symptoms or motor symptoms. The study should be based on combinations of clinical, genetic, imaging, and laboratory data.
REFERENCE
- Jadiya P, Chatterjee M, Sammi SR, Kaur S, Palit G, Nazir A. Sir-2.1 modulates 'calorie-restriction-mediated' prevention of neurodegeneration in Caenorhabditis elegans: implications for Parkinson's disease. Biochem Biophys Res Commun. 2011;413(2):306-310. doi:10.1016/j.bbrc.2011.08.092
- He R, Yan X, Guo J, Xu Q, Tang B, Sun Q. Recent Advances in Biomarkers for Parkinson's Disease. Front Aging Neurosci. 2018;10:305. Published 2018 Oct 11. doi:10.3389/fnagi.2018.00305
- Srivastava S, Haigis MC. Role of sirtuins and calorie restriction in neuroprotection: implications in Alzheimer's and Parkinson's diseases. Curr Pharm Des. 2011;17(31):3418-3433. doi:10.2174/138161211798072526
- Reeve A, Simcox E, Turnbull D. Ageing and Parkinson's disease: why is advancing age the biggest risk factor?. Ageing Res Rev. 2014;14(100):19-30. doi:10.1016/j.arr.2014.01.004
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