See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/325906320

Parkinson’s Disease

Article · March 2018

CITATIONS READS
0 48

5 authors, including:

Anam Shehzadi Zahid Anwar

University of Gujrat University of Gujrat
2 PUBLICATIONS   0 CITATIONS    57 PUBLICATIONS   892 CITATIONS   

SEE PROFILE SEE PROFILE

Akash Raza
University of Gujrat
7 PUBLICATIONS   3 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Biotechnology View project

Hyperproduction of commercial cellulases View project

All content following this page was uploaded by Akash Raza on 21 June 2018.

The user has requested enhancement of the downloaded file.

 International Journal of Applied Biology and Forensics (2018) 2(1): 175-179
Copyright © 2018 All Rights Reserved
ISSN: 2520-7318 (Online) | 2520-730X (Print)

REVIEW ARTICLE OPEN ACCESS

Parkinson’s Disease
Anam Shehzadi1, Kanza Razzaq2, Muhammad Tahir3, Zahid Anwar4 and *Akash Raza5

1, 3, 4, 5
Department of Biochemistry and Biotechnology, University of Gujrat, Pakistan
2
Department of Biotechnology, Virtual University, Pakistan
*Correspondence: akash.raza@gmail.com

ABSTRACT

The second most common neurodegenerative movement disorder among elderly individuals is Parkinson’s disease (PD).
PD is characterized clinically by tremors, rigidity, slowness of movement, and postural imbalance. Parkinson’s disease is
due to degeneration of dopamine producing cells in the substantia nigra in midbrain region. Parkinson's disease can be
caused by rare familial genetic mutations. Several genes when mutated have been shown to cause familial Parkinsonism,
but in majority of cases it is likely to result from an interaction between multiple genetic and environmental factors.
Therapeutic strategies used for treating Parkinson’s disease focus primarily on reducing the severity of its symptoms using
dopaminergic medications. Pharmacotherapy with levodopa for Parkinson's disease provides symptomatic benefit.
Dopamine agonists are also helpful and, when taken with low doses of levodopa, often provide sustained benefit with fewer
side effects.

Keywords: Parkinsonism, Neural Degeneration, Substantia nigra, Dopamine, α-synuclein, Levodopa.

How to Cite: Shehzadi A, Razzaq K, Tahir M, Anwar Z, Raza A. 2018. Parkinson’s disease. International Journal of Applied Biology and Forensics 2:
175-179

Published: March, 2018

Copyright Statement: An open-access article distributed under Creative Commons Attribution License, with unrestricted use, distribution, and
reproduction in any medium, crediting the original author and source.
Funding Statement: No funding statement
Competing Interests: The authors have declared that no competing interests exist.

Volume 2 | Issue 1 | Page 175


Introduction
Parkinson's disease is a common, progressive,
debilitating disease with substantial physical, psycho-
logical and social implications (Worth PF 2013).
Parkinson disease (PD) is the second most common form
of neural degeneration among elderly individuals (Mihael
H et al. 1997) and the most common neurodegenerative
movement disorder which needs attention. In these two
centuries since it was first described by James Parkinson,
we have learned a great deal about the disorder.
Parkinson's disease is part of a group of conditions called
motor system disorders, which are associated with the
loss of dopamine-producing brain cells. These dopamine-
associated motor disorders are referred to as
Parkinsonism. PD is clinically characterized by tremors,
rigidity, slowness of movement, and postural imbalance
(Lang AE and Lozano AM 1998).
Parkinson’s disease is thought to affect more
than 1 million people in the United States alone, 1 of every
100 individuals above the age of 55. Parkinson's disease
(PD) is a common neurodegenerative disorder and has a
lifetime incidence of approximately 2 percent. It is one of
the most common movement disorders in the world which
affects approximately 1% of all adults over the age of 60.
Parkinson’s disease is due to degeneration of dopamine
producing cells in the substantia nigra in the midbrain
(Smeyne M and Smeyne RJ 2013). Arvid Carlsson
pointed to the loss of dopamine as the principal deficit in
PD and to levodopa as the mode of pharmacotherapy
(Nguyen LT 2013).
Causes of Parkinson’s disease
Parkinson's disease is such a slowly progressive
disorder that affects movement, muscle control, and
balance. PD develops when cells get destroyed in certain
parts of the brain stem, particularly the crescent-shaped
cell mass known as the substantia nigra (Lang AE and
Lozano AM 1998). Fibers are sending out from nerve cells
in the substantia nigra to tissue located in both sides of
the brain. Essential neurotransmitters are then released
from the cells present there that help control movement
and coordination. Nerve cells present in the substantia
nigra send out fibers to the corpus stratia, which is gray
and white bands of tissue located in both sides of the
brain. There the cells release dopamine, an essential
neurotransmitter (a chemical messenger in the brain).
Loss of dopamine in the corpus stratia is the primary
defect in Parkinson's disease. Dopamine deficiency is the
hallmark feature in PD (Lotharius and Brundin 2002).
It is one of three major neurotransmitters known
as catecholamines, which help the body respond to stress
and prepare it for the fight-or-flight response. Loss of
dopamine negatively affects the nerves and muscles
controlling movement and coordination, resulting in the
major symptoms characteristic of Parkinson's disease.
Shahzadi A et al. 2018
Dopamine also appears to be important for efficient
information processing, and deficiencies may also be
responsible for problems in memory and concentration
that occur in many patients. The accumulation of α-
synuclein, ubiquitin and other proteins in Lewy bodies in
degenerating dopaminergic neurones in substantia nigra
in idiopathic Parkinson's disease (PD) suggest that
inhibition of normal/abnormal protein degradation may
contribute to neuronal death (Kevin S et al. 2001).
In patients who died with Parkinson's disease,
polyunsaturated fatty acid (PUFA) levels (an index of the
amount of substrate available for lipid peroxidation) were
measured in several brain regions and then age-matched
control human postmortem brains. PUFA levels were as
a result reduced in parkinsonian substantia nigra
compared to other brain regions and to control tissue.
However, an increased level of lipid peroxidation
continues to occur in the parkinsonian nigra up to the time
of death, perhaps because of continued exposure to
excess free radicals derived from some endogenous or
exogenous neurotoxic species (Nguyen LT 2013). The
defective sequestration of dopamine into vesicles which
leads to the generation of reactive oxygen species in the
cytoplasm, is a key event in the demise of dopaminergic
neurons in Parkinson's disease, and it might represent a
common pathway that underlies both genetic and
sporadic forms of the disorder (Lotharius and Brundin
2002).
Genetic Basis of Parkinson’s disease
There is a striking loss of dopamine-producing
neurons in the substantia nigra neuropathologically,
which is accompanied by depletion of dopamine in the
striatum. Although most forms of PD are sporadic, though
in some cases familial inheritance is observed. In the late
1990s, two mutations in the α-synuclein gene were linked
to rare, autosomal dominant forms of PD. Rare forms of
early-onset PD have been linked to mutations in α-
synuclein and parkin. In 1997, a missense mutation in the
α-synuclein gene, located in chromosome 4q21–23,
which led to an alanine-to-threonine conversion at amino
acid 53 (A53T) was reported in a large Greek/Italian
kindred. One year later, a second missense mutation in
α-synuclein resulting in an alanine-to-proline substitution
at residue 30 (A30P) in a family of German origin was
reported. These mutations have not been found in other
patients with familial PD, but single-nucleotide
polymorphisms (SNPs) in the promoter region of α-
synuclein have been associated with an increased risk for
the disease. While Mutations in the parkin gene have
been associated with autosomal recessive, juvenile-onset
PD (Kitada T et al. 1998). Subsequently parkin mutations
were detected in cases of autosomal recessive early
onset (<45 years) parkinsonism, in isolated young onset
cases presenting as fairly typical Parkinson’s disease and
in familial cases with an age at onset of symptoms as late
Volume 2 | Issue 1 | Page 176
 Shahzadi A et al. 2018

Table 1: Major nonmotor symptoms (NMS) in PD

Neuropsychiatric Symptoms Depression, Anxiety, Apathy, Hallucinations, Delusions, Illusions, Delirium (may be
drug induced), Cognitive Impairment (dementia, MCI), Dopaminergic Dysregulation
Syndrome (usually related to levodopa) and Impulse Control Disorders (related to
Dopaminergic Drugs)

Sleep Disorders REM Sleep Behaviour Disorder (possible premotor symptoms), Excessive Daytime
Somnolence, Narcolepsy Type “Sleep Attack”, Restless Legs Syndrome, Periodic Leg
Movements, Insomnia, Sleep Disordered Breathing and non-REM Parasomnias
(Confusional Wandering)
Fatigue Central fatigue (may be related to dysautonomia) and peripheral fatigue
Sensory Symptoms Pain, Olfactory Disturbance, Hyposmia, Functional Anosmia and Visual Disturbance
(Blurred Vision)
Autonomic Dysfunction Bladder Dysfunction (Urgency, Frequency, Nocturia), Sexual Dysfunction (may be
drug-induced), Sweating Abnormalities (Hyperhydrosis) and Orthostatic Hypotension
Gastrointestinal Symptoms Dribbling of Saliva, Dysphagia, Agueusia, Constipation, Nausea and Vomiting
Dopaminergic Drug-Induced Hallucinations, Psychosis, Delusions, Dopamine Dysregulation Syndrome and Impulse
Behavior NMS Control Disorders
Dopaminergic Drug-Induced Ankle Swelling, Dyspnea, Skin Reactions, Subcutaneous Nodules and Erythematous.
other NMS

Non-Motor Fluctuations Dysautonomia, Cognitive/Psychiatric, Sensory/Pain and Visual Blurring

Other Symptoms Weight Loss and Weight Gain

(Chauduri KR et al. 2006)

as 64 years (Abbas N et al. 1999, Klein C et al. 2000,
Lucking C et al. 2000).
In a further recent paper, the French Parkinson’s
disease Genetics Study Group and the European
Consortium on Genetic Susceptibility in Parkinson’s
disease report finding parkin mutations in 10 of 30 families
screened with early onset autosomal recessive
parkinsonism (Rawal N et al. 2003). Parkin is an E3
ubiquitin‐protein ligase that targets specific substrates for
degradation through the ubiquitin‐proteasome pathway
(Shimura H et al. 2000). One of its substrates is a
glycoslyated form of α‐synuclein, perhaps providing a link
between parkin and idiopathic Parkinson’s disease
(Hardy J et al. 2003). Typical Lewy bodies were only
detected in the substantia nigra and locus coeruleus when
neuropathological examination has been reported in a few
parkin mutation cases (Farrer M et al. 2001). Hardy J et
al. (2003) have recently speculated on a possible
mechanism underlying the reported absence of typical
highly ubiquitinated Lewy bodies in parkin disease.
disease is likely to result from an interaction between
multiple genetic and environmental risk factors but can
also be caused by rare familial genetic mutations. Over
recent years, many variants in a growing number of genes
have been identified which are involved in the
pathogenesis of Parkinson's disease. Mutations in
several genes have been shown to cause familial
Parkinsonism. Some of them are SNCA, LRRK2, Parkin,
PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, UCHL1,
GIGYF2, HTRA2, and EIF4G1. Additionally, six genes
have been shown conclusively to be risk factors for
sporadic Parkinson's disease, and are also discussed
(GBA, MAPT, BST1, PARK16, GAK, and HLA). Many
more genes and genetic loci have been suggested, but
need confirmation. There is evidence that pathways
involved in the rare familial forms also play a role in the
sporadic form, and that the respective genes might also
be risk factors for sporadic Parkinson's disease (Gasser
and Thomas 2005).
Pathogenesis of Parkinson disease

The complete loss of function of parkin, may
occur due to deletion of an allele which then leads to cell
death in the absence of Lewy body formation, while
incomplete loss of function of parkin, may occur due to
point mutations in the gene, which result in Parkinsonism
with Lewy body formation. In most cases Parkinson's
Another broad field includes pathways that are
involved in aberrant protein degradation and proteasomal
and lysosomal dysfunction. Our knowledge about the
pathogenesis of Parkinson’s disease is growing due to the
discovery of new genes in conjunction with animal studies
(Lotharius and Brundin 2002).

Volume 2 | Issue 1 | Page 177


Signs and Symptoms
Parkinson’s disease is a neurodegenerative
disorder whose cardinal features are bradykinesia,
resting tremor, muscular rigidity, gait disturbances and
postural reflex impairment. Although Parkinson focused
entirely on motor symptoms, we have come to realize that
the disorder is much more complex and includes panoply
of psychiatric symptoms as well. Non-motor symptoms of
Parkinson’s disease constitute a major clinical challenge,
as they are common, yet often overshadowed by the
dominance of motor symptoms and high awareness of
these among treating health care professionals (Chauduri
KR et al. 2006).
Treatment
Few neurological diseases like Parkinson’s
disease have received much attention and investment in
research. Although great strides have been made in the
development of agents to treat this neurodegenerative
disease, but none address the underlying problem
associated with it that is the progressive loss of
dopaminergic neurons. Therapeutic strategies used for
the treatment of Parkinson’s disease these days focus
primarily on reducing the severity of its symptoms using
dopaminergic medications. These agents are burdened
by adverse effects and long-term complications though
providing substantial benefit (Stacy S and Steven J 2005).
Pharmacotherapy with levodopa for Parkinson's disease
provides symptomatic benefit, but fluctuations in (or loss
of) response may eventually occur. Dopamine agonists
are also helpful and, when taken with low doses of
levodopa, often provide sustained benefit with fewer side
effects; novel agonists and new methods for their
administration are therefore under study (Aminoff MJ
1994). Although dopamine supplementation is currently
used for PD as a means to replace the diminished tone of
dopaminergic output from substantia nigra pars
compacta, it only alleviates the symptomatic motor
dysfunction, and its effectiveness declines as the disease
progresses. Therefore, it is essential to develop suitable
animal models that can be used for the screening and
testing of new therapeutic strategies targeting the actual
pathogenic process as opposed to merely developing
symptomatic therapies. Genes linked to rare forms of PD
or the processes that they regulate are potential
therapeutic targets (Gasser and Thomas 2005).
Both pharmacologic and nonpharmacologic
interventions play an important role in the comprehensive
management of this disorder (Agid Y and Lancet 1991).
Other therapeutic strategies including the use of type B
monoamine oxidase inhibitors to reduce the metabolic
breakdown of dopamine, catechol-O-methyltransferase
inhibitors to retard the breakdown of levodopa,
norepinephrine precursors to compensate for deficiency
of this neurotransmitter, glutamate antagonists to
counteract the effects of the subthalamic nucleus, and
Shahzadi A et al. 2018
various neurotrophic factors to influence dopaminergic
nigrostriatal cells are being explored (Aminoff MJ 1994).
Conclusion
Parkinson disease is a neurodegenerative
disorder resulting from the death of dopamine producing
cells in the substantia nigra. The pathology of the disease
is characterized by the accumulation of a protein called α
-synuclein into inclusions called Lewy bodies in neurons.
Shaking, rigidity, slowness of movement and difficulty with
walking and gait are the most obvious symptoms of this
disease. Levodopa and dopamine agonists are used for
the treatment of Parkinson’s disease and these are
effective at managing the early motor symptoms of the
disease.
References
Abbas N, Lucking CB, Ricard S, Durr A, Bonifati V,
Michele G. 1999. A wide variety of mutations in the
parkin gene are responsible for autosomal
recessive parkinsonism in Europe. Hum Mol Genet
8: 567-574.
Agid Y, Lancet. 1991. Parkinson’s disease.
Pathophysiology 337: 1321-1327.
Aminoff MJ. 1994. Treatment of Parkinson’s disease.
West J Med 161: 303-308.
Chauduri KR, Healy D, AHV S. 2006. The non-motor
symptoms of Parkinson’s disease. Diagnosis and
management. Lancet Neurology 5: 235-245.
Farrer M, Chan P, Chen R, Tan L, Lincoln S, Hernandez
D. 2001. Lewy bodies and parkinsonism in families
with Parkin mutations. Ann Neurol 50: 293-300.
Gasser, Thomas. 2005. Genetics of Parkinson’s disease.
West J Med 18: 363-369.
Hardy J, Cookson MR, Singleton A. 2003. Genes and
parkinsonism. Lancet Neurol 2: 221-228.
Kevin S, McNaught, Jenner P. 2001. Proteasomal
function is impaired in substantia nigra in
Parkinson’S disease. 297 3: 191-194.
Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura
Y, Minoshima S. 1998. Mutations in the parkin gene
cause autosomal recessive juvenile parkinsonism.
Nature 392: 605-608.
Klein C, Pramstaller PP, Kis B, Page CC, Kann M, Leung
J. 2000. Parkin deletions in a family with adult‐
onset, tremor‐dominant parkinsonism: expanding
the phenotype. Ann Neurol 48: 65-71.
Lang AE, Lozano AM. 1998. Parkinson’s disease. N Engl
J Med 339: 1044-1053.
Lotharius, Brundin. 2002. Pathogenesis of parkinson's
disease: dopamine, vesicles and synuclein. Nature
Reviews Neuroscience 3: 932-942.
Lucking C, Durr A, Bonifiati V, Vaughan J, De Michele G,
Grassor T. 2000. Association between early onset
Parkinson’s disease and mutations in the parkin
gene. New Engl J Med 342: 1560-1567.
Volume 2 | Issue 1 | Page 178
 Shahzadi A et al. 2018

Mihael H, Lavedan, Leroy. 1997. Mutation in the α- Smeyne M, Smeyne RJ. 2013. Glutathione metabolism
Synuclein Gene Identified in Families with and Parkinson disease. Free Radical Biology and
Parkinson's Disease. Clin Med 276: 2045-2047. Medicine 8: 257-263.
Nguyen LT. 2013. The Beneficial Role of Thiamine in Stacy S, Steven J. 2005. Treatment of Parkinson
Parkinson Disease. CNS Neurosci Ther 6: 1207- Disease. West J Med 19: 723-743.
1211. Worth PF. 2013. How to treat Parkinson’s disease in
Rawal N, Periquet M, Lohmann E, Lucking CB, Teive HA, 2013. Clin Med 13: 93-96.
Ambrosia G. 2003. New parkin mutations and
atypical phenotypes in families with autosomal
recessive parkinsonism. Neurology 60: 1378-1381.
Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S,
Minishima S. 2000. Familial Parkinson’s disease
gene product, parkin, is a ubiquitin‐protein ligase.
Nature Genet 25: 302-305.

Volume 2 | Issue 1 | Page 179

View publication stats