Parkinson’s disease: Is there a light at the end of a tunnel?

doi:10.4236/apd.2013.24022

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Vol.2, No.4, 116-117 (2013) Advances in Parkinson’s Disease

http://dx.doi.org/10.4236/apd.2013.24022

Parkinson’s disease: Is there a light at the end of a

tunnel?

Andrei Surguchov

VA Medical Center and Kansas University Medical Center, Kansas City, USA; [email protected]

Received 22 August 2013; revised 22 September 2013; accepted 30 September 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Parkinson’s disease is the second most common neu-

rodegenerative disorder after Alzheimer disease affecting

1% - 2% in people >60 years old and 3% - 4% in people

>80. It is a chronic, progressively disabling neurodegen-

erative disorder that occurs late in life, causing motor,

cognitive, autonomic and emotional symptoms. There are

four cardinal features of PD: tremor at rest, rigidity, aki-

nesia (or bradykinesia) and postural instability [1]. The

motor symptoms of Parkinson’s disease result from the

death of dopamine-generating cells in the substantia ni-

gra, a region of the midbrain.

The cost of Parkinson’s disease is substantial, includ-

ing reduced quality of life, lost productivity, and in-

creased health care expenditures. The number of persons

with Parkinson’s disease worldwide is expected to dou-

ble by 2030 due to the aging of the population.

In the majority of cases (~95%), the disease occurs

sporadically and is caused by the specific loss of dopa-

minergic neurons within the substantia nigra pars com-

pacta. The identification of rare highly penetrant muta-

tions in genes causing familial form of Parkinson’s dis-

ease has had a considerable impact on our understanding

of the pathogenesis of this complex and common disor-

der.

One of the hallmarks of the Parkinson’s disease is the

presence of Lewy bodies located basically in the sub-

stantia nigra. Lewy bodies are composed of different

proteins including an aggregation prone protein



-synu-

clein [2], and other proteins, e.g. synphililin-1, ubiquitin,

neurofilaments and molecular chaperones. In addition to

Lewy bodies,



-synuclein in the brain of patients is pre-

sent in the form of soluble oligomeric aggregates which

possess toxic properties. Since Parkinson’s disease is as-

sociated with the aberrant accumulation of



-synuclein,

it is referred to a group of synucleinopathies.

Our understanding of the genetic bases of Parkinson’s

disease has been enhanced by a number of large ge-

nome-wide association (GWA) studies which have col-

lectively identified variants at over 18 loci that signifi-

cantly increase the risk for this disorder.

At present, there is no cure for PD, but a variety of

medications provide dramatic relief from the symptoms.

Medical therapy for Parkinson’s disease is most effective

in treating the motor symptoms of resting tremor, bra-

dykinesia, and rigidity. Levodopa remains the most ef-

fective current treatment for motor symptoms. Neurosti-

mulation of the subthalamic nucleus is recommended for

the management of motor fluctuations and dyskinesia in

patients with advanced Parkinson’s disease and severe

motor complications.

Usually, patients are given levodopa combined with

carbidopa. Carbidopa delays the conversion of levodopa

into dopamine until it reaches the brain. Nerve cells can

use levodopa to make dopamine and replenish the brain’s

dwindling supply. Although levodopa helps at least three-

quarters of parkinsonian cases, not all symptoms respond

equally to the drug. Bradykinesia and rigidity respond

best, while tremor may be only marginally diminished.

Problems with balance and other symptoms may not be

alleviated at all. Anticholinergics may help control tre-

mor and rigidity. Other drugs, such as a potent agonist at

dopamine D2 receptors bromocriptine, dopamine ago-

nists pramipexole and ropinirole, mimic the role of do-

pamine in the brain, causing the neurons to react as they

would to dopamine. An antiviral drug, amantadine in-

creases dopamine release, blocks dopamine reuptake and

also reduces symptoms. In May 2006, the FDA approved

rasagiline to be used along with levodopa for patients

with advanced PD or as a single-drug treatment for early

PD.

Neurotrophic factors (also known as trophic or growth

factors) are among the promising potential treatments to

slow, stop or reverse Parkinson’s disease in the brain. In

pre-clinical models of Parkinson’s disease, these proteins

have been shown to promote the survival of dopamine

neurons, as well as to induce these neurons’ regrowth,

which could have implications for slowing or stopping

the progression of the disease rather than just temporarily

A. Surguchov / Advances in Parkinson’s Disease 2 (2013) 116-117 117

masking symptoms. However, the use of neurotrophic

factors is sometimes limited by the poor pharmacological

properties, including the low blood-brain barrier perme-

ability and relevant side effects. Development of small

molecules with agonist activity, with better pharmacoki-

netics, and less side effects, is an attractive possibility.

The exciting news about the mechanism of Parkin-

son’s disease comes from basic research concerning the

structure and function of



-synuclein. Growing evidence

indicates a causative role of misfolded forms of the pro-

tein in this disorder, including the results of immunopa-

thology and genetics.



-Synuclein has long been defined

as a” natively unfolded” monomer with molecular weight

of about 14 kDa. A publication from Dennis Selkoe’s

group [3] states that



-synuclein might exist in the brain,

erythrocytes and other human cells as a folded tetramer

of 58 kDa caused a lot of discussions. Disputing the

tetrameric



-synuclein as a predominant form in the hu-

man tissue, the researchers from Thomas Sűdhof group

have presented evidence that the brain



-synuclein pri-

marily consists of an unstructured monomer, but readily

aggregates in a time-dependent manner [4].

Another interesting finding which might be important

for better understanding of



-synuclein role in patho-

genesis of the Parkinson’s disease is its prion-like prop-

erties. According to recent findings, misfolded



-synu-

clein can induce Lewy-like pathology in cells that can

spread from affected to unaffected region [5]

The significance of recent basic results in the field of

Parkinson’s disease and related neurodegenerative dis-

eases gives us a hope that decades of discoveries pave

the way for therapeutic breakthroughs. It is anticipated

that latest findings will lead to new, efficacious treat-

ments for the treatment of this devastating disorder.

REFERENCES

[1] Jankovic, J. (2008) Parkinson’s disease: Clinical features

and diagnosis. Journal of Neurology, Neurosurgery &

Psychiatry, 79, 368-376.

http://dx.doi.org/10.1136/jnnp.2007.131045

[2] Surguchov, A. (2008) Molecular and cellular biology of

synucleins. International Review of Cell and Molecular

Biology, 270, 225-317.

http://dx.doi.org/10.1016/S1937-6448(08)01406-8

[3] Bartels, T., Choi, J.G. and Selkoe, D.J. (2011) α-Synu-

clein occurs physiologically as a helically folded tetramer

that resists aggregation. Nature, 477, 107-110.

http://dx.doi.org/10.1038/nature10324

[4] Burré, J., Vivona, S., Diao, J., Sharma, M., Brunger, A.T.

and Südhof, T.C. (2013) Properties of native brain α-

synuclein. Nature, 498, E4-E6

http://dx.doi.org/10.1038/nature12125

[5] Olanow, C.W. and Brundin, P. (2013) Parkinson’s disease

and alpha synuclein: Is Parkinson’s disease a prion-like

disorder? Movement Disorders, 28, 31-40.

http://dx.doi.org/10.1002/mds.25373