First described as “Shaking Palsy” by James Parkinson in 1817, Parkinson’s disease (PD) is a chronic progressive and devastating degenerative neurological illness, second only to Alzheimer’s disease (AD) in its scope. It affects about 2% of the population over the age of 50 years, with estimated 1.5 million Americans afflicted by the disease. An estimated 60,000 Americans are diagnosed with PD each year, which means one American is given the diagnosis of PD roughly every 8.5 minutes. There are no effective clinical diagnostics and therapeutics available for PD. Current medications only treat symptoms, do little to treat the disease and stop working after sometime, leaving the patient helpless to fight the disease.
2. PATHOLOGY AND CLINICAL SYMPTOMS
On a pathological basis, PD is characterized first by the progressive and profound loss of dopamine-producing neurons, also known as dopaminergic neurons, in a part of the brain known as the substantia nigra. Dopamine is a neurotransmitter with many functions in the brain, including important roles in behavior and cognition, voluntary movement, and motivation. Secondly, the appearance of protein fibrillars, also known as Lewy bodies (LBs), inside neurons. Although neuronal loss in the substantia nigra is pronounced, there is also widespread neurodegeneration in the central nervous system (CNS).
Clinically, most patients have a motor dysfunction and suffer from slowness of movement, resting tremor, muscular rigidity, poor balance, and often also show autonomic, cognitive and psychiatric disturbances. PD is a progressive disease and while a patient may survive 10-20 years (or more) after diagnosis, lack of effective treatment for the disease leads to years of slow deterioration of the CNS and eventually to premature death.
The etiology of PD is not fully understood, but it is believed to be caused by both environmental and genetic factors:
3.1. ENVIRONMENT FACTORS
There is some evidence that certain toxins in the environment may cause Parkinson’s disease. Scientists have suggested that external or internal toxins may selectively destroy the dopaminergic neurons, causing Parkinson’s disease. Toxins that may be linked to Parkinson’s include manganese, carbon monoxide, carbon disulfide, and some pesticides such as MPTP. In addition, it is believed that oxidative stress can cause Parkinson’s disease. Oxidation is a process in which free radicals (unstable molecules lacking one electron), in an attempt to replace the missing electron, react with other molecules (such as iron). Free radicals are normally formed in the brain and body, but in a neurologically healthy person there are mechanisms to scavenge them. In people with Parkinson’s disease, these mechanisms may be defective. It is also possible that environmental toxins may contribute to abnormal free radical formation and lead to Parkinson’s disease.
3.2. GENETIC FACTORS
Epidemiological studies have demonstrated that although the majority of PD cases are sporadic, about 10% have a strict genetic link to them. The discovery of genes linked to familial forms of PD during the last decade have confirmed the role of genetics in development of PD, and have provided vital clues in understanding the molecular pathways leading to the sporadic form of PD. These genetic breakthroughs have provided us with unique information about some key proteins involved in the pathogenesis of PD, encouraging scientists to develop technologies to modulate the function of such proteins, which may lead to the development of revolutionary treatment for this debilitating disorder.
To date, about 16 Parkinson’s disease related genetic loci, known as the PARK loci, and 11 genes associated with these PARK loci have been identified. Among these genes, 5 have been studied extensively. These genes are: α-synuclein (also known as SNCA), parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7) and LRRK2 (PARK8). Recent genome-wide association studies have found that individuals acquiring any of these variants have strong chances of developing PD.
3.2.i. α-Synuclein A native unfolded protein, α-synuclein is believed to play a role in recycling of neurotransmitter vesicles (storage and compartmentalization of neurotransmitters), and is also associated with vesicular and membranous structures. Structurally, the protein consists of 140-amino acid. The first big breakthrough came in 1997 when three point mutations were identified in several families with a history of PD. Since then, α-synuclein has been a protein under extensive investigation by several research groups around the world. Individuals with three point mutations in α-synuclein tend to get PD at a younger age (between 40 to 50 years of age) compared to those who acquire only two mutations or one mutation in the faulty gene. Both pathogenic mutations and elevated concentrations give α-synuclein a propensity to polymerize into oligomers and higher order aggregates such as fibrils, which are toxic to dopamine-producing neurons. Neuronal death occurs by several mechanisms such as rupture of plasma membrane and mitochondrial (energy “Power-House” of a cell) damage. In addition, overproduction of α-synuclein, either native or mutant, can block or slow the release of dopamine and other neurotransmitters stored in vesicles. With release significantly impaired, dopamine can accumulate to toxic levels, forming dopamine quinine, which damages the neurons.
Mutations in the parkin gene are the most frequent known cause of early-onset ( Pathologically, parkin mutations are associated with loss of dopaminergic neurons. Cell loss in patients with parkin-induced PD appeared to be caused by a loss of function of the protein, which is to ligase ubiquitin with another protein
for clearance by proteolytic enzymes. Mutations in parkin impair its ligase (an enzyme that joins two molecules, especially in living organisms) activity, resulting in insufficient substrate clearance and subsequent aggregation.
Loss-of-function due to mutations in PINK1 is the second most common cause of autosomal recessive early onset Parkinsonism, the mutation frequency varies geographically from 0 to 15% worldwide. Most mutations in PINK1 are point mutations or small insertions or deletions. PINK1 mutations are also a rare cause of sporadic early-onset PD.
Mutations in DJ-1 gene are the least common of the known causes of autosomal recessive Parkinsonism (~1% of early- onset PD). A large deletion and a mutation, L166P, were first identified in DJ-1 in two consanguineous families from Netherland and Italy.
The major breakthrough in PD came in 2004 with the addition of LRRK2 (Leucine-rich repeat kinase 2) to the list of PD causing genes. Mutations in the LRRK2 have been identified as a genetic cause of familial and the more common sporadic form of PD. Out of the 20 LRRK2 mutations identified, the most prevalent mutation, LRRK2 (G2019S), located within the kinase domain of LRRK2, is present in more than 85% of PD patients carrying LRRK2 mutations, with R1441C/G (within the GTPase domain) the next most prevalent, at approximately 10%. In addition, the G2019S was observed in 4% of all familial PD cases, ~2.0% of sporadic PD cases, suggesting the link of the mutation to the etiology of PD. Tremor in PD is more frequently observed in individuals with LRRK2 (G2019S) mutation. Remarkably, it accounts for PD in 29% of Ashkenazi Jews and 37% of North African Arabs. Although there is conflicting data on other mutations such as R1441C, Y1699C, and I2020T, LRRK2 G2019S mutation has consistently shown to be more neurodegenerating than the native protein. Also, LRRK2 G2019S is primarily associated with brainstem Lewy body pathology, reminiscent of typical, late-onset idiopathic PD. The risk of PD with a LRRK2 G2019S mutation increases with age; it is 28% at age 59 years, 51% at age 69 years, and 74% at age 79 years.
4. HURDLES IN DEVELOPING DIAGNOSTICS AND THERAPEUTICS FOR PD
The slow progress in developing non-invasive clinical diagnostics and therapeutics for PD has been due to two main reasons:
i. Limited understanding of etiology
ii. Impermeability of the blood-brain barrier (BBB)
Our understanding of the molecular pathways leading to the development of PD has improved significantly over the last 1-2 decades. Pathogenic proteins have been identified. However, the impermeability of the BBB has been an insurmountable global medical problem in the way of developing novel non- invasive diagnostics and therapeutics not only for PD but also for other diseases of the central nervous system. In its natural protective role, the BBB protects the CNS from blood-born foreign substances such as viruses, bacteria and parasites. When something goes wrong with the CNS, treatment is usually not available because most pharmaceuticals cannot cross the BBB into the CNS. The irony is that although the hurdles of the BBB have been recognized for several decades, the progress made to overcome these hurdles has been dismal. That is why, as of today, there is no diagnosis and/or cures for the diseases of the CNS.
The government organizations and private foundations have been spending taxpayers’ money to fund research which so far has failed to address immediate problems of the patients’ sufferings from debilitating diseases of the CNS. Unless, there is a public awareness about the challenges of delivering drugs to the CNS, individuals who will be diagnosed with neurodegenerative diseases, now and in the future, will continue meeting the same ill fate of slow and gradual total deterioration of the CNS with complete dependency on loved ones and early death.
With a patent pending, there is a company that has developed a novel technology to transport drugs across the Blood-Brain Barrier. Its technology has been validated in Alzheimer’s-like transgenic mice by a renowned UCSD neuroscientist, who successfully targeted amyloid-plaque in the CNS of transgenic mice. The company is certain that its technology will be beneficial in diagnosing and treating PD by removing and preventing the formation of Lewy bodies through direct targeting of the oligomeric and fibril forms of a-synuclein and related kinases.
As an Organization that has constantly looked for the Ultimate Quality of Life for people living with Parkinson’s,Parkinson’s Resource Organization is excited by this firm’s potential and is actively working in support of bringing this science to realization.
Parkinson’s Disease, A Collaborative