Parkinson disease

Parkinson disease, named after Doctor James Parkinson, who first described it, is a progressive neurodegenerative condition characterized by the gradual loss of dopamine-producing neurons in a brain region called the substantia nigra.

Long before the time of Doctor Parkinson, signs of this condition appeared in ancient tales. In Homer’s Odyssey, King Nestor, once a fierce and fearless warrior, slowly changed with age. His hands started to tremble, his steps became sluggish, and his body became stiff, so he could no longer join the battle. His story sounds all too familiar to what we today recognize as Parkinson disease.

Now, to understand what was going on with King Nestor, we need to look deep within the brain, specifically at the basal ganglia. The basal ganglia play a major role in carrying out learned motor plans, such as riding a bike to university. Moreover, they help fine-tune and shape movement while also controlling unwanted or unnecessary motor activity. Basal ganglia do this by modulating signals from the motor part of the thalamus to the motor cortex. Once those signals reach the motor cortex, they travel down the spinal cord to activate muscles, so you can spin those wheels and make it to pathology class on time. At the same time, basal ganglia help regulate muscle tone and help maintain posture.

The basal ganglia include the striatum, which consists of the caudate nucleus and putamen; the globus pallidus; the subthalamic nucleus; and the substantia nigra. When it comes to Parkinson disease, the most important player is the substantia nigra. This phrase literally means black substance and originates from its dark appearance, which comes from melanin-rich neurons. You can picture it as a strong shot of espresso tucked into your midbrain, small, dark, and packed with power.

Now, the substantia nigra consists of two parts. The pars reticulata receives signals from the striatum and sends them down to the thalamus, using the inhibitory, calming neurotransmitter GABA. This helps keep your movements steady and prevents unwanted motions from slipping through. On the other hand, the pars compacta contain dopamine-producing neurons that project to the striatum. This connection forms the nigrostriatal pathway, which supplies the striatum with dopamine and helps initiate movement. Without enough dopamine flowing through it, even simple actions, like reaching for your favorite chocolate bar, can become difficult.

In Parkinson disease, the dopamine-producing neurons in the pars compacta slowly die off. As the brain loses more of these neurons over time, it sends weaker signals through the nigrostriatal pathway, which impairs the initiation and control of voluntary movements.

While most of the time, the underlying cause is unknown, we know that several genetic mutations are associated with Parkinson disease. Based on the type of mutation, we can classify Parkinson disease into autosomal dominant and autosomal recessive types.

Autosomal dominant types are associated with mutations in the SCNA gene, which encodes alpha-synuclein that enables neurons to communicate with each other. When the SCNA gene mutates, the cell produces abnormal alpha-synuclein that misfolds and accumulates within neurons, eventually forming Lewy bodies. These round, eosinophilic structures are the hallmark of Parkinson disease. Next, there’s the LRRK2 gene, which encodes leucine-rich repeat kinase 2, an enzyme that's important with intracellular signaling. When this gene mutates, the enzyme stops working, causing various cellular functions to malfunction.

On the flip side, in the autosomal recessive types, we have mutations of the PARK7 gene, which encodes DJ-1 protein; PINK1 gene, which encodes PINK1 protein; and PARK2 gene, which encodes Parkin protein. These proteins are essential for normal mitochondria functioning. When these proteins don’t work as they should, mitochondrial dysfunction sets in, eventually leading to cell damage and death.

It’s also important to remember that some people with Parkinson disease carry mutations in the GBA1 gene. This gene makes an enzyme called glucocerebrosidase, which helps lysosomes break down and clear out cellular waste. When the enzyme doesn’t work properly, cellular waste accumulates, disrupting normal cell processes and eventually causing cell death. These same mutations are known to cause a lysosomal storage disorder called Gaucher disease. However, we are still not sure how this mutation increases the risk of Parkinson disease.

Regardless of the underlying genetic mutation and type, the loss of melanin-rich neurons causes substantia nigra to look much paler than usual. It’s like pouring milk into that cup of espresso tucked in the brain.

As dopamine-producing neurons die off, dopamine levels in the nigrostriatal pathway gradually decline. With less dopamine available, the brain struggles to initiate movement, which results in clinical features we call parkinsonism. Parkinsonism is a clinical syndrome that includes bradykinesia, rigidity, tremor, and postural instability.