Is Parkinson’s Disease One Disease Entity? | Brain Blogger

Is Parkinson’s Disease One Disease Entity? | Brain Blogger

Silhouette of elderly man

We hear of Parkinson’s disease very often these days. This is indeed a
very common neurological disorder affecting about 6 million people
worldwide. The disease is characterized by a selective loss of
dopaminergic neurons in certain parts of the brain. That causes muscle
rigidity, tremors, bradykinesia (slowness of movement) and problems in

Decades of research brought some treatments that can delay the onset
of Parkinson’s disease and try to counterbalance the endogenous dopamine
deficit. Unfortunately, we still don’t have a treatment capable to stop
the neuronal death and provide cure for the disease.

The current mainstream treatments for Parkinson’s disease were
introduced around thirty years ago. They focused on dopamine systems and
motor symptoms of advanced disease, and included dopatherapy with
dopamine agonists and a monoamine oxidase B inhibitor selegiline. More
agonists and inhibitors were introduced over the years, but the basic
approach did not change. Parkinson’s disease still remains a serious
condition leading to disability. Newer molecular targets, bio-markers
and better understanding of molecular mechanisms of this condition are

The fact that our understanding of Parkinson’s disease is very
limited is clearly indicated by the fact that not all patients respond
to the existing treatments such as levodopa, major dopamine agonist in
clinical practice. Part of the answer to the question why some patients
respond to the existing treatments and others don’t lies in the fact
that Parkinson’s disease is really an umbrella term for a number of
conditions with similar symptoms. Diagnosis of disease is still based on
the descriptive definition provided by James Parkinson almost 200 years
ago.  The conditions covered by this description, however, are not all
the same and can be caused by very different genetic and environmental
factors. This has obvious implications for the development and
application of any potential drugs targeting the disease.

Small portion (about 10%) of all Parkinson’s cases are related to
genetics. Mutations in several genes were identified as risk factors in
the development of the condition. The involvement of three genes,
Parkin, PINK1 and DJ1, in the disease pathogenesis seems to be linked to
their neuroprotective properties. They encode proteins that counteract
oxidative stress, prevent damage to mitochondrial DNA and are essential
for effective work of the ubiquitin-proteasome system. However, this is
not specific for the Parkinson’s disease. These three gene products play
equally critical role in a wide spectrum of neurodegenerative
disorders. Is there anything more specific that can cause Parkinson’s
disease, rather than any other neurodegeneration, in either humans or

It seems that Parkinson’s disease pathogenesis requires not only the
genetic susceptibility, but also environmental exposures to harmful
chemicals and ageing. Genetic factors alone are not enough to cause the
disease. In 90% of cases, the disease is sporadic without any clear
genetic basis.

Current evidences suggest that oxidative stress, abnormal protein
aggregation and mitochondrial disfunction are possible early triggers of
cell death in Parkinson’s disease.  Parkinson’s disease can be induced
by mitochondrial toxins MTPT and its metabolite MPP+, as well as
pesticides rotenone and paraquat in both animals and humans.

Lewy bodies are abnormal aggregates of proteins observed inside the
nerve cells of Parkinson’s patients. The formation of alpha-synuclein
and tau inclusions in Lewy bodies in certain neurons is the most
distinctive anatomical feature of the disease. Cell death in Parkinson’s
disease is connected to both oxidative stress and accumulation of
alpha-synuclein. Abnormal accumulation of alpha-synuclein can also
produce oxidative damage to both mitochondria and dopamine.

However, neither Lewy bodies nor alpha-synuclein and tau inclusions
are exclusive for Parkinsonism. They are seen in the broad spectrum of
other neurologic condition broadly classified as synucleopathies,
tauopathies and Lewy body disorder on the basis of presence of the above
characteristic features. In Parkinson’s disease, these individual
pathological features can be present in some patients and absent in

It seems that more diagnostic categories will be required in the
future to properly characterize the sub-classes of Parkinson’s disease.
What is now called “Parkinsonism” can include clinical Parkinson’s
Syndrome, Lewy Body Parkinson’s Disease, several Lewy Body disorders and
 synucleinopathies, and taupathies with various aetiology.

The Queen Square Brain Bank for Neurological Disorders (QSBB) has
issued the list of criteria that should be used for clinical diagnostics
of Parkinson’s disease. It includes (a) clinical diagnostics criteria,
(b) genetic testing for mutations in alpha-synuclein gene SNCA in
patients with family history of disease; mutations in  leucine-rich
repeat kinase 2 (LPRK2) and  glucocerebrosidase (GPA) in sporadic
patients; testing of parkin, PINK1 and DJ-1 in patients with early onset
of the condition, with additional testing of several genes if these
come out negative, (c) panel of various tests (neuroimaging), and (d)
response to levodopa. This long list alone is in itself a manifestation
of the fact that Parkinson’s disease can be caused or triggered by a
variety of factors and therefore cannot be considered as just a single
disease entity.

In the diagnostics of Parkinsonism, the DNA analysis must become a
compulsory element. Improved sub-typing on the basis of genetic data
might improve the prediction of possible disease outcome. A red tulip, a
symbol of the disease, should make researchers and clinicians to
consolidate their efforts in developing and refining therapies to
conquer this devastating illness.