Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons and accumulation of Lewy’s bodies leading to imbalance in the levels of dopamine. PD is the second frequent neuro disorder following Alzheimer’s disease. Symptoms of PD include tremors, bradykinesia, muscle stiffness, impaired posture and gait, loss of movement, changes in speech, changes in writing, thinking difficulties, constipation, depression, sleep problems, changes in blood pressure, smell dysfunction and pain and fatigue. The levels of norepinephrine at neuron ends, which control many automatic functions of the body are also affected, leading to non-movement features.1 It is a slowly progressing neurodegenerative disorder with no exact cause identified, with symptoms similar to other neurodegenerative diseases such as multiple system atrophy, progressive supranuclear palsy, striatonigral degeneration. This makes it difficult to identify PD at an early stage.2, 3
Approximately 10 million people worldwide live with PD. The cost of PD is estimated to be close to $52 billion every year in the United States alone with nearly one million expected to be living with Parkinson's disease by 2020. PD is generally diagnosed above the age of 60, with 1% of the population diagnosed during their 60s or later.4, 5
The symptoms of PD are classified as motor and non-motor symptoms, with symptoms getting progressively worse as the disease develops.
PD progresses in five stages, with non-motor and motor skills degenerating rapidly with the progression to the next stage.
Stage 1: Initially there are mild symptoms that do not affect normal life. Examples include tremors, changes in posture, and movement symptoms occurring on one side of the body.
Stage 2: Movement symptoms begin to progress to both sides of the body, with visible changes in gait and walking. Symptoms begin to affect daily routines, making them more difficult and time-consuming.
Stage 3: The movements become slower and there is more frequent loss in balance. While the patient is still able to live on his own, daily tasks such as eating become significantly impaired by PD.
Stage 4: Standing becomes difficult with patients requiring support of a walker. Symptoms are very severe, and patients cannot live alone.
Stage 5: This is the most advanced stage of PD, with little or no leg function. The patient experiences frequent hallucinations and delusions, and requires round-the-clock care.9
PD is characterized by a loss in dopaminergic neurons in the substantia nigra pars compacta, located in the midbrain. The pathological hallmark of PD is the aggregation of α-synuclein in the form of Lewy bodies and Lewy neurites, the underlying mechanism of which involves the following:
Structure of α-synuclein
α -synuclein is a presynaptic neuronal protein encoded by gene SNCA. The SNCA gene encodes a 140 amino acid protein which in aqueous solution is present as stable tetramers that resist aggregation. The protein does not have a defined tertiary structure. It is mostly unfolded, and is called as natively unfolded protein.
α -synuclein protein is composed of three distinct regions (Fig.1):
Fig. 1. Schematic representation of human α-synuclein depicting: (source)
(a) SNCA gene structure, (b) mRNA, and (c) protein domains.
Synuclein family of proteins consist of 3 forms namely α, β, δ among which only α-synuclein is predominant as compared to other forms. α -synuclein differs structurally from the NAC region. On binding to lipids such as phospholipids, and other negatively charged lipids, it forms α-helical structures.Under a prolonged period of incubation, it produces β-sheet-rich amyloid-like structure which aggregates resulting in different forms such as unfolded monomers, soluble oligomers, protofibrils, and high molecular weight insoluble fibrils. (Fig.2)
Fig. 2. formation of α-synuclein oligomers enriched in β-sheet structures (source)
α -synuclein possesses two low complexity domains and undergoes liquid–liquid phase separation. α -synuclein in the presence of a molecular crowder, which is promoted further by various PD-associated conditions. This was addressed by using Simple Modular Architecture Research Tool (SMART) and IUPred2 algorithms which exposed that α -synuclein droplets undergo a liquid to solid-like transition, leads to hydrogel formation that comprises fibrillar aggregates and oligomers. α -synuclein forms liquid droplets even within cells and consequently transforms into solid-like aggresomes, which is regulated by microtubules. These events collectively establish that phase separation acts as an initial step towards α -synuclein aggregation associated with PD pathology.10
Degradation of α-synuclein (protein clearance) occurs through Ubiquitin-Proteasome System, Molecular chaperones involving Heat shock proteins or Autophagy lysosomal pathway as represented by Fig.3.
Fig. 3. Protein clearance pathway (source)
α-synuclein, in association with tubulin proteins such as tau proteins, plays a key role in cytoskeletal dynamics. During the misfolding of α -synuclein, tau proteins are hyperphosphorylated resulting in neuroinflammation and neurotoxicity.11, 12
α-synuclein is known to regulate the production of dopamine through interaction with tyrosine hydroxylase Phenylalanine or tyrosine, which is the precursor for Dopamine synthesis via sequential reactions catalyzed mainly by phenylalanine hydroxylase (PH), tyrosine hydroxylase (TH), and DOPA decarboxylase. It can also be synthesized from tyramine via a minor pathway by CYP2D6. Dopamine is effectively degraded into the main inactive metabolites DOPAC and homovanillic acid (HVA) via a series of reactions mediated predominantly by the enzymes monoamine oxidase (MAO), catechol-O-methyl transferase (COMT), and aldehyde dehydrogenase (ALDH), and ADH. The dopamine metabolism and clearance mechanism is presented in Fig.4.
Fig. 4. Metabolic pathway of dopamine synthesis and clearance (source)
Many factors could trigger the onset of PD, ranging from environmental conditions, genetic factors or the type of gut microbes existing in the person’s intestine. The loss of nigrostriatal dopaminergic innervation causes PD. Other risk factors could include gender (men are more susceptible to PD than women) and age (most patients diagnosed with PD are over the age of 60).13, 14
Genetic Risk Factors
Researchers have identified a few specific genes that could be attributed to the development of PD; however, they are very rarely seen, such as in cases where many members of the family are diagnosed with PD. There are specific genes, however, which can increase the chances of PD.15
Environmental risk factors
Gut microbiome: The association between impaired gastrointestinal mobility and high PD-specific pathology is poorly understood. However, from recent studies it is known that gut microbiota is required for many neurological functions, such as motor function, microglia function, and α-synuclein pathology.
Braak's Hypothesis explains the reason why non-motor symptoms are typically the first to emerge. The medulla is responsible for involuntary actions, such as sneezing, and olfactory bulb is responsible for the sense of smell. Braak's Hypothesis states that PD originates in these parts of the brain and progresses to the substantia nigra over time. A pathogen which causes sporadic PD could enter the body through nasal tract or may be present in the gut (Prevotellaceae bacteria is relatively high in patients with PD). Once it has entered the nasal tract, it is swallowed, causing Lewy pathology in the nasal as well as digestive tract. The pathogen then proceeds from the nasal cavity to the olfactory bulb or through the vagal nerve, finally causing Lewy pathology in the brain which results in PD.17
Oxidative stress theory states that antioxidants present in the brain need to be broken down and oxidized. The antioxidants create oxidative stress, which has been found to be significantly higher in patients with PD. In PD, there is a deficiency of dopamine (DA), which is an inhibitory neurotransmitter. This stimulates a chain of reactions leading to the opening of neural gates responsible for the control of Ca++ ions. The Ca++ ions spill out of the neuron, damaging mitochondria and creating further oxidative stress in the brain, making DA neurons more susceptible to neurodegeneration.18
Imaging is used to confirm clinical diagnosis of symptoms such as muscular rigidity, rest tremor or postural instability.
|Biological marker||Tracer used||Technique|
|Metabolism of levodopa||18F-dopa||PET|
|Presynaptic dopamine transporter||11C-CFT, 18F-CFT, 11C-RTI-32, 18F-FP-CIT, 11C-methylphenidate||PET|
|123I-β-CIT, 123I-FP-CIT, 123I-altropane, 99mTc-TRODAT-1||SPECT|
Fig. 5. Scan of brain; Control vs. Parkinson patients (source)
Therapeutic options for treating Parkinson’s disease include pharmacotherapeutic interventions involving drug or drug combinations as well as non-pharmacotherapeutic interventions involving surgeries, neurostimulations etc.
The most prevalent treatment for PD is highly symptomatic.. The available treatments involve increasing the level of dopamine in the neuronal endings as proposed below:
Disease modifying therapy for treatment of PD involves inhibition of misfolding and/or aggregation of α-synuclein.
Such trials have not been successful so far because of following challenges:
Repurposed drugs involves examination of existing drugs for new therapeutic purposes so as to provide quick results in a cost effective manner. Existing drug development approaches include extensive efforts towards identifying mechanism of action of new drug candidates which result in agents or drugs, considered to be ‘non-specific’ when more than one unrelated enzyme or protein is affected at similar concentrations. Based on this principle repurposed drugs are recent emergents in treating diseases such as PD. FDA approved repurposed drugs are being tested for treating PD.22
Mechanisms of potential therapies for repurposed drugs:
Fig.6 represents the proposed mechanisms for cellular therapies and small molecules.
Fig. 6. cellular therapies in PD (source)
Symptomatic motor therapy using viral vector-mediated targeted delivery of genes encoding proteins involved in dopamine production such as aromatic-l-amino acid decarboxylase, or basal ganglia network modulation such as glutamate decarboxylase, are under study.
Dopaminergic cells derived from human pluripotent stem cells, which may be either human embryonic stem cells or induced pluripotent stem cells, are regarded as cellular therapies for PD and are currently facing challenges on account of ethical issues.
Transplantation of mesencephalic fetal dopaminergic neurons into the striatum of patients with PD has also been observed to improve motor symptoms and reduce the disorders in movement.27
Immunotherapies targeting α-synuclein are a new focus for clinical testing. Since the introduction of levodopa, there are major advances in the field of PD treatment. Disease modifying therapies with chemical entities along with regenerative approaches such as stem cells and gene therapies, are significant improvements that have taken place in recent times.28
On the whole, curative therapy for PD involves disease halting mechanism, restorative therapy, and neuroprotective agent with different methods involved in each approach. A schematic presentation of such approaches is presented in Fig.7.
Fig. 7. Schematic representation of curative therapies
Surgical treatment of Parkinson’s disease has made significant progress over the past 70 years, however, its effectiveness is limited to motor symptoms which include bradykinesia, rigidity, tremor and medication-induced dyskinesia. There has been rapid progress in surgical interventions varying from the lesioning procedure to the more recent deep brain stimulation and other techniques such as optogenetics, magnetogenetics, and sonogenetics. A general representation of progress in surgical approaches is presented in Fig.8.29
Fig. 8. Schematic representation of surgical approaches for PD treatment
The clinical trial data presented below gives an idea of the status of new drugs that are likely be launched in the near future. (Table 1)
|Sponsors / Collaborators||Drug name||Phase||Date of start to estimated end date|
|Pharma Two B Ltd.||P2B001||Phase 3||January 29, 2018 to February 28, 2021|
|Sunovion||APL-130277||Phase 3||August 31, 2015 to March 1, 2023|
|Takeda Pharmaceuticals||TVP-1012 (Rasagiline)||Phase 3||February 3, 2015 to September 29, 2016|
|Sponsors / Collaborators||Drug name||Phase||Date of start to estimated end date|
|Hoffmann-La Roche with Prothena Biosciences Limited||RO7046015 ( prasinezumab )||Phase 2||June 27, 2017 to April 17, 2026|
|Biogen||BIIB054||Phase 2||January 10, 2018 to June 21, 2021|
|Astrazeneca with Covance MMS Holdings, Inc Catalent||MEDI1341||Phase 1||October 17, 2017 to January 19, 2021|
|Lundbeck with Genmab||Lu AF82422||Phase 1||July 25, 2018 to December 2020|
|United Neuroscience Ltd. With Centre for Human Drug Research, Netherlands Worldwide Clinical Trials||UB-312||Phase 1||August 29, 2019 to June 30, 2021|
|Neuropore Therapies Inc. With Celerion||NPT520-34||Phase 1||May 5, 2019 to October 9, 2019|
|Neuropore Therapies Inc. With UCB S.A. - Pharma Sector||NPT200-11||Phase 1||July 2015 to February 2016|
Table 2. On-going clinical studies for new drugs32, 33
*In 2017 Takeda pharmaceuticals submitted a New Drug Application (“NDA”) to the Ministry of Health, Labour and Welfare in Japan for rasagiline mesylate (TVP-1012). No information is available on its approval.
A few clinical trials that failed during phase 3 are given below:
Many start-up companies are currently working on alleviating PD, a few of which are listed below.
A patent search was conducted to identify innovative approaches adopted by researchers for diagnosis / treatment of PD.
Parkinson’s disease poses a big challenge to researchers due to individual patient heterogeneity as well as its progressive nature. The knowledge of genetic risk factors arising from LRRK2 (leucine rich repeat kinase 2), and mutations in the GBA gene etc. are laying the foundation for the development of precision medicine. New therapeutic targets and more accurate diagnostic agents are being developed to identify precisely the root cause of the disease. In treatment, there is a shift from symptomatic treatment to disease modifying treatment with more focus on reducing the spread of α-synuclein pathology. Special focus is being directed towards neuroprotection and also development of agents to enhance neuronal survival. Possible causes such as immunomodulation and gut microbiome are also gaining research attention.