Parkinson’s disease, which is sometimes called Parkinson disease, Parkinson’s,
or PD, is a movement disorder where the dopamine-producing neurons in the substantia nigra of the brain
Parkinson’s is one of the most common neurological disorders.
It’s a progressive, adult-onset disease, and it gets more common with age.
Most of the time, there’s no known cause.
But in a few cases, there might be a genetic cause, like mutations in the PINK1, parkin,
or alpha synuclein genes, and in rare cases, Parkinsonian symptoms may be caused by MPTP,
a toxic impurity that can be found in the recreational drug MPPP or desmethylprodine,
which is a synthetic opioid.
In other people, one or more risk factors, rather than a single outright cause, might
contribute to Parkinson’s, for example pesticide exposure or DNA variants in genes like LRRK2.
No matter the cause is, Parkinson’s derives from the death of dopamine-producing, or dopaminergic,
neurons in the substantia nigra.
The name substantia nigra means “black substance,” since it is darker than other brain regions
when you look at a slice of the brain on an autopsy.
We usually refer to the substantia nigra as if it’s in a single location, but there
are actually two of these regions in the brain, one on each side of the midbrain.
The substantia nigra is a part of the basal ganglia, a collection of brain regions that
control movement through their connections with the motor cortex.
In Parkinson’s, these darkened areas of substantia nigra gradually disappear.
Under a microscope, Lewy bodies, which are eosinophilic, round inclusions made of alpha-synuclein
protein are present in the affected substantia nigra neurons before they die.
The function of alpha-synuclein is unknown, as well as the significance of Lewy bodies,
and they are both found in other diseases like Lewy body dementia and multiple system
The substantia nigra actually can be split into two sub-regions.
First, there’s the pars reticulata, which receives signals from another part of the
basal ganglia called the striatum, which is a term for the caudate and putamen put together,
and relays messages to the thalamus via neurons rich in the neurotransmitter GABA, also known
as gamma-aminobutyric acid.
Second, there’s the pars compacta, and this is the part of the substantia nigra affected
The pars compacta sends messages to the striatum via neurons rich in the neurotransmitter dopamine,
forming the nigrostriatal pathway, which helps to stimulate the cerebral cortex and initiate
Therefore, when substantia nigra pars compacta neurons die, the individual may be in a hypokinetic
or low movement state which is commonly seen in Parkinson’s.
In addition to simply initiating movements, the substantia nigra helps to calibrate and
fine tune the way that movements happen, which leads to the clinical features of Parkinson’s.
First there’s tremor, which is an involuntary shakiness most noticeable in the hands—characteristically
called a “pill-rolling” tremor because it looks like someone rolling a pill between
their thumb and index finger.
This is a “resting tremor,” meaning it is present at rest and diminishes with intentional
Next there’s rigidity, which refers to stiffness that can appear as “cogwheel” rigidity,
which is when there are a series of catches or stalls as a person’s arms or legs are
passively moved by someone else.
Rigidity is also responsible for the stooped posture and an almost expressionless face
that some individuals with Parkinson’s might have.
Next up is Bradykinesia is slow movement, hypokinesia is lessened movement, and akinesia
is an absence of movement, and all three result from difficulty initiating movements.
Examples of this are having the legs freeze up when trying to walk and also walking with
a shuffling gait, or small steps.
Finally, a late feature of the disease is postural instability which causes problems
with balance and can lead to falls.
Despite these multiple effects on movement, Parkinson’s Disease does not produce weakness.
This helps differentiate it from diseases that affect the motor cortex or corticospinal
In addition, the resting tremor of Parkinson’s Disease helps to differentiate it from cerebellar
diseases, which might result in an action or intention tremor, which is a tremor that’s
essentially the opposite of a resting tremor, where the tremor actually gets worse with
Also, both bradykinesia and postural instability help differentiate Parkinson’s from essential
Of which an action tremor is also a hallmark feature.
Non-motor brain functions can be affected in Parkinson’s as well, leading to additional
common symptoms including depression, dementia, sleep disturbances, and difficulty smelling.
These are thought to come about because of dysfunction in dopaminergic signalling in
other parts of the brain beyond the substantia nigra, for example in the prefrontal cortex
leading to cognitive symptoms, and also possibly from issues with other neurotransmitters like
Fortunately, there are treatments that help with Parkinson’s symptoms, although none
stop the progressive neurodegeneration.
The main strategy here is to increase the amount of dopamine signalling in the brain.
Dopamine itself can’t cross the blood-brain barrier, but its precursor levodopa can, and
once in the brain, levodopa is converted to dopamine by dopa decarboxylase, most importantly
within the remaining nigrostriatal neurons.
Peripheral dopa decarboxylase also exists, which can metabolize levodopa into dopamine
before it gets through the blood brain barrier, and—via additional enzymes—metabolize
it into other catecholamines like epinephrine, which can cause unwanted side effects like
This is exactly why levodopa is administered with carbidopa, a dopa decarboxylase inhibitor
that isn’t able to cross the blood-brain barrier.
Another strategy is using amantadine, which is also an antiviral medication that increases
endogenous dopamine production, although the mechanism here is still being worked out.
A different strategy is to use dopamine agonists that can stimulate dopamine receptors and
basically trick the brain into thinking there’s more dopamine than there really is, like bromocriptine,
which is an ergot or fungal derivative, as well as pramipexole and ropinirole, which
are not ergot derivatives.
Alright the next dopamine-directed class of therapies are inhibitors of COMT, catecholamine-O-methyltransferase,
which is an enzyme that degrades dopamine and levodopa.
COMT inhibitors like entacapone and tolcapone are only given with levodopa to prevent the
enzyme from breaking it down outside the central nervous system, thus allowing more of it to
enter the brain.
. Very similarly, there are medications like selegiline which inhibits monoamine oxidase
B, also known as MAO-B, which is another enzyme that metabolizes dopamine.
Since usually there’s this balance of signaling between dopamine and acetylcholine, a loss
of dopamine reaching the striatum increases the relative amount of acetylcholine signalling
Therefore anticholinergics can be given to restore the balance of cholinergic and dopaminergic
signaling, like benztropine, which improves the tremor of PD.
A special treatment available to help treat PD is deep-brain stimulation.
Which involves an implantable device that directly sends electrical signals to the basal
ganglia which counteracts the aberrant signaling in Parkinson’s.
The term “parkinsonism” is sometimes used to describe symptoms of Parkinson’s that
are seen in other nervous system diseases like Lewy body dementia, Wilson disease, and
Pick disease, as well as side effects of a medication, like antipsychotics such as haloperidol,
which blocks dopamine receptors, and metoclopramide, a dopamine antagonist sometimes used to treat
Alright, as a quick recap—Parkinson’s is a progressive movement disorder caused
by degeneration of dopamine-producing neurons in the substantia nigra, specifically in the
pars compacta, which leads to resting tremor, rigidity, problems initiating movement, and
postural instability, and for which therapy primarily focuses on increasing brain dopamine.