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Parkinson’s Disease (Nalls, 2019)

STUDY TITLE: Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies

SUMMARY: Identification of 90 genetic variants associated with Parkinson’s disease.

OVERVIEW:  Parkinson’s disease is a neurodegenerative disorder caused by reduced dopamine signaling in some regions of the brain that leads to tremors. This can impair various activities that involve muscle movements including walking, speaking and eating. To date, Parkinson’s disease remains largely a genetic mystery. To advance our understanding of genetic risk factors for Parkinson’s, this study analyzed the genomes of almost 1.5 million individuals of European ancestry and identified 90 genetic variants, of which 38 were novel. Many variants were in genes that are active in regions of the brain involved in movement control. The study also identified genetic associations between Parkinson’s and smoking as well as Parkinson’s and educational attainment.

DID YOU KNOW? Diets rich in antioxidants, omega-3 fatty acids and vitamin D3 and CoQ10 are believed to reduce the risk of Parkinson’s disease. Reducing stress and exercising may also help. [SOURCE]

SAMPLE RESULTS: Learn more about the Nebula Research Library.

PARKINSON’S-ASSOCIATED VARIANTS: rs356182, rs356203, rs34637584, rs35749011, rs34311866, rs62053943, rs199453, rs356228, rs7225002, rs1474055, rs7221167, rs10847864, rs5019538, rs10513789, rs823118, rs76904798, rs4698412, rs117896735, rs112485576, rs17686238, rs199351, rs1867598, rs12456492, rs76763715, rs11557080, rs35643925, rs873786, rs6854006, rs117073808, rs11150601, rs3802920, rs4101061, rs2251086, rs13294100, rs10756907, rs10797576, rs11158026, rs1293298, rs117615688, rs4653767, rs620513, rs57891859, rs141128804, rs9912362, rs896435, rs73038319, rs11683001, rs13117519, rs3104783, rs4140646, rs6658353, rs138017112, rs6808178, rs55961674, rs850738, rs72840788, rs2248244, rs6497339, rs9267659, rs979812, rs181609621, rs2295545, rs75859381, rs10221156, rs11707416, rs12497850, rs12528068, rs11610045, rs144755950, rs62333164, rs12283611, rs34025766, rs55818311, rs1450522, rs2269906, rs2904880, rs61169879, rs10748818, rs6825004, rs12951632, rs4771268, rs26431, rs6500328, rs997368, rs3742785, rs7938782, rs666463, rs114138760, rs11578699, rs6476434, rs11950533, rs77351827, rs12600861, rs6875262, rs9568188, rs2280104, rs76116224, rs2042477, rs8087969, rs76949143, rs4954162, rs9261484, rs1941685, rs2086641, rs11658976, rs12147950, rs7134559

ADDITIONAL RESOURCES:
Parkinson’s disease
The role of dopamine

WEEKLY UPDATE: November 16, 2019

Parkinson’s Disease

The Parkinson’s disease is a slowly progressive loss of nerve and brain cells. The characteristic symptoms are akinesia, rigor and rest tremor. As an incurable neurodegenerative disease, it belongs to the degenerative diseases of the extrapyramidal motor system. Approximately one percent of the world’s population over 60 years of age is affected by this disease, making Parkinson’s disease the second most common neurodegenerative disease in the world (after Alzheimer’s disease).

Parkinson’s disease is characterized by the predominant death of dopamine-producing nerve cells in the substantia nigra, a structure in the midbrain. The lack of a messenger substance called dopamine ultimately leads to a reduction in the activating effect of the basal ganglia on the cerebral cortex and thus to movement disorders. Deep brain stimulation (DBS) is the most commonly performed surgical treatment for Parkinson’s.

The leading symptoms are:

  • Disturbance of the sense of smell
  • mood swings (mild irritability) with mild depression
  • Constipation
  • the disturbance of dream sleep by atypical strong movements during REM sleep
  • motor disease in the main stage (low dopamine level)
  • Muscle tremor at rest, especially as a rhythmic tremor of the extremities,
  • “out-of-round” movement when running for a longer time
  • muscle rigidity or inelastic increased resting tension,
  • slowed movements, which can lead to immobility, and
  • Postural instability.

The current definition of Parkinson’s syndrome requires that the cardinal symptom bradykinesis or akinesia occurs in combination with at least one of the other symptoms (rigor, tremor, or postural instability). In addition, various sensitive, vegetative, psychological and cognitive disorders are possible.

To date, there is still no possibility of causal treatment of Parkinson’s syndrome, so only treatment of the symptoms is possible. As the disease progresses, several drugs are often combined, which must be taken at increasingly shorter intervals in order to achieve sufficient efficacy and avoid fluctuations in efficacy. Advanced therapy options include continuous apomorphine infusion, continuous L-dopa infusion or deep brain stimulation.

Parkinson's Disease: Symptoms and Early Warning Signs of PD
Deep Brain Stimulation, Source

Epidemiology

The disease usually begins between the ages of 50 and 79 (peak 58 to 62 years). A Parkinson’s syndrome can rarely occur before the age of 40. In the age group 40 to 44 years about one in 10,000 people is living with Parkinson.

The manifestation rate of the disease increases with increasing age until about the age of 75, then it decreases again.

Of those over 80 years of age, about 1.5-2.0 percent suffer from Parkinson’s syndrome and have a decrease in quality of life. In the United States, approximately 60,000 Americans are diagnosed with Parkinson’s each year. There are 10 million cases of Parkinson world wide.

Causes

Dopamine deficiency

Parkinson’s disease is a degenerative disease of the extrapyramidal motor system (EPS) or basal ganglia. It involves the death of nerve cells in the pars compacta of the substantia nigra, which produce dopamine and transport it through their axons into the putamen. The first signs of disease are only noticed when approx. 55% to 60% of these dopaminergic cells have died.

Parkinson's Disease: Is Gene Therapy the Answer We Have Been Looking For? |  ASGCT - American Society of Gene & Cell Therapy
Causes of Parkinson’s, Source

The dopamine deficiency ultimately leads to an imbalance in the function of the basal ganglia in two ways. The messenger substance glutamate is relatively abundant. The globus pallidus internus ultimately inhibits the motor activation of the cerebral cortex by the thalamus. This leads to the main symptoms rigor, tremor and hypokinesia, but also to a slowing of mental processes (bradyphrenia).

In addition to the dopamine deficiency, changes in other neurotransmitters have also been observed. For example, serotonin, acetylcholine and norepinephrine deficiency was found in some regions of the brain stem.

Pesticides and Parkinson's disease - Clinical Advisor
Causes of Parkinson’s, Source

Is Parkinson’s Genetic?

Research and identification of the inherited forms have shown that Parkinson’s disease (MP) is not a uniform disease, but a heterogeneous group of diseases with a spectrum of clinical and pathological manifestations (PARK1 to PARK13). Monogenic forms of Parkinson’s disease are responsible for about five to ten percent of all patients with Parkinson’s disease.

Among these, genetic mutations of the alpha-synuclein gene (SNCA gene, PARK1) are of particular interest, since alpha-synuclein (SNCA) is the major component of what is called Lewy bodies in familial and sporadic Parkinson’s disease.

The PARK1 locus was mapped in a large family with dominant inherited Parkinson’s disease and Lewy body pathology; two other point mutations with high penetrance were identified in large families but not in patients with sporadic Parkinson’s disease.

Remarkably, in 2007, SNCA aggregates were identified in a specific part of the brain called the presynaptic fraction of human brain tissue. Possibly as an expression of early synaptic dysfunction, although the exact relationship between aggregation, cellular dysfunction and cell death is not yet known.

In addition to changes in the amino acid sequence, however, duplications and triplications also lead to an increase in the protein’s tendency to form oligomers and fibrillary aggregates, so that the regulation of SNCA expression and translation plays an important, at least modulating role.

Changes in regulatory regions of the SNCA gene could also be associated with a higher risk of developing Parkinson’s disease. Several studies have found associations of different genetic variants (single nucleotide polymorphisms; SNP) in the promoter region and other sequence segments of the SNCA gene with sporadic Parkinson’s disease (PD Gene Database). Studies from 2008 suggest a possible association of single SNPs also in the non-coding sequence with the SNCA expression level.

More recent studies also suggest an autoimmune component. For example, the detection of α synuclein peptides, which as antigens under laboratory conditions led to the activation of previously identified frequently altered MHC molecules, was successful. Some of the most significant findings on the role of the α synuclein in the development of the disease at the cellular level have been obtained from experiments with genetically modified breeding lines of the nematode Caenorhabditis elegans.

The majority of cases , about 85%, of Parkinson aren’t hereditary. However, people who get early-onset Parkinson’s disease are more likely to have inherited it. Having a family history of Parkinson’s disease may increase the risk that you will get it. Having a first-degree family member with Parkinson’s raises the risk to 3 percent. Mutations in lrrk2 are the most inherit cause of Parkinson’s disease. lrrk2 genes are responsible for 5% of familial Parkinson’s cases.

Genetic testing for Parkinson’s Disease typically looks for mutations in the genes: GBA, PARK7, SNCA, LRRK2, parkin and PINK1.

Environmental Factors

As external triggers of Parkinson’s disease, certain toxins, so-called neurotoxins, which damage the substantia nigra, play a role in the diagnosis. These were usually ingested by those affected, either in the course of their work or as environmental toxins.

In California in the early 1980s, the intravenous consumption of pethidine contaminated with MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine) caused Parkinson-like symptoms in young drug addicts after a short time, which could be successfully treated with L-dopa (see below). The effect of MPTP is that it is converted in the brain into the actively toxic molecule MPP+ (1-methyl-4-phenylpyridinium).

This molecule is similar in structure to a dopamine molecule, so that it can enter the dopamine-producing nerve cells via the dopamine transport system. As the MPP+ accumulates in the cells, it increasingly unfolds its toxic effect by suppressing important metabolic processes there.

Against this background, the herbicide paraquat is suspected to increase the risk of Parkinson’s syndrome. Paraquat is structurally very similar to MPP+. Studies conducted in Canada have shown a correlation between the use of large quantities of paraquat and a far above-average number of Parkinson’s cases in the population of the region in question.

Another pesticide that is considered to cause Parkinson’s is the insecticide rotenone. In animal experiments it could be shown that the uptake of rotenone leads to the release of alpha-synuclein (SNCA), a protein produced naturally in the body that, analogous to MPP+, has a toxic effect on dopamine-producing nerve cells and can cause their degeneration.

In France, Parkinson’s disease has been recognized as an occupational disease of farmers since 2012 if they have been in contact with pesticides for at least ten years.

In addition, cleaning agents containing trichloroethylene and perchloroethylene, Octenol, a natural metabolic product of moulds, craniocerebral traumas (SHT; “closed head/brain injuries”) and infections, have been also been known to cause Parkinson’s.

Symptoms of Parkinson

The disease begins insidiously and then progresses throughout the patient’s life, the symptoms become stronger in the course of the disease and are therefore easier to recognize. Idiopathic Parkinson’s syndrome typically begins unilaterally (and remains more severe in the course of its progression); early signs include reduced and later missing swinging of an arm while walking. It is not uncommon for shoulder pain and unilateral muscle tension to occur, which first leads the patient to an orthopaedic surgeon.

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Symptoms of Parkinson’s, Source

Parkinson’s syndrome is defined by the presence of bradykinesis or akinesia, This general lack of motor symptoms is a prerequisite for the diagnosis of a Parkinson’s syndrome, and one of the three other leading symptoms (rigor, tremor, postural instability)

Rigor

This refers to muscle stiffness due to an increase in muscle tone. It is caused by an involuntary tension of the entire striated musculature and often leads to muscle pain. Visible on the outside is a slight flexion of the elbow joint, trunk and neck and later of the knee joints.

Passive movement of the joints of the upper and lower extremities gives rise to the so-called cogwheel phenomenon, in which it appears that the movement in the elbow joint runs over a cogwheel that brakes the movement at alternating intervals. [38] Muscle groups close to the body are often more severely affected (axial rigor). A curved malposition of the trunk of the body due to the increase in tone is known as camptocormia

Rest tremor

Mutual tension of opposing muscles causes a relatively slow tremor (antagonist tremor – four to six beats per second, rarely up to nine beats per second), which decreases with movement. It is typical for idiopathic Parkinson’s syndrome (75%) and less typical for atypical Parkinson’s syndrome (25%), the tremor is also unilaterally accentuated. Tremor is the most obvious symptom, but it also occurs as an essential tremor or in cerebellar disorders, so that it can lead to misdiagnosis.

Postural instability

People with Parkinson have reduced stability when holding the body upright is caused by a disturbance of the positional reflexes. The small but fast reflex compensatory movements are delayed, resulting in gait and standing insecurity.

The turning movement becomes unsteady and the patients start to trip. They become afraid of falling; this fear of falling can impair them in addition to their motor disability. If the positioning reflexes are severely impaired at an early stage, an atypical Parkinson’s syndrome must be considered.

Additional symptoms linked to Parkinson disease include:

  • Sensitivity symptoms
  • Sensory disturbances (dysesthesias)
  • Pain occurs particularly in joints and muscles (see above).
  • Vegetative disorders
  • An ointment face (greasy, shiny facial skin) results from increased sebum production (together with hypomimia in the context of existing akinesia).
  • circulatory regulation disorders (orthostatic hypotension) occurs as a result of the increase in tonus.
  • Rest tremor
  • slow tremor
  • Postural instability
  • sleep problems
  • balance problems

For additional information, clinical trial information, and treatment options, visit the Parkinson Foundation.

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