When around 70% of dopaminergic neurons have died off, people experience the first overt symptoms of Parkinson’s disease.

These neurons produce dopamine, an important messenger molecule (“neurotransmitter”) which neurons in the brain use to communicate with each other, especially neurons involved in movement.

So to properly treat people with Parkinson’s, and even reverse the disease, it’s very important to “bring back” these lost cells.

One way to achieve this is by using stem cells or other cells (e.g. dopamine-producing cells) and to introduce them into the brain area where most cells are lost, namely the substantia nigra.

Some companies are working on creating stem cells, which are then differentiated (changed) into cells that produce dopamine. These cells are then infused into the brain (the substantia nigra).

Scientists discovered that actually using cells that are in between stem cells and differentiated dopamine-producing cells could actually work better than injecting stem cells or dopaminergic cells.

These “hybrid” or “in-between” cells are called “dopaminergic precursor cells” or “dopaminergic precursor cells”.

What also has become more clear in recent years, is that it’s more effective to protect the injected cells.

Most cells, when injected into the brain, die off due to the sudden change in environment and stress. Also, very few cells graft properly.

An important reason for this is that the cellular environment in the brain is pro-inflammatory, pro-oxidative and “aged" (most Parkinson patients are old, and inflammation also plays a role in Parkinson’s disease). This causes many injected cells to not properly graft and die.
Therefore, embedding the cells into gels that protect them, or first (genetically) modifying the cells before they are injected, leads to better survival and grafting of the cells.

Mitochondrial dysfunction plays a central role in the pathogenesis of Parkinson's disease. Mitochondria are crucial for energy production and regulating cellular health.

In Parkinson’s disease, impaired mitochondrial function leads to reduced energy (ATP) production, increased oxidative stress, and the release of harmful reactive oxygen species (ROS).

This dysfunction contributes to the degeneration of dopaminergic neurons in the substantia nigra, a hallmark of Parkinson's disease.

Additionally, mutations in genes like PINK1 and Parkin, involved in mitochondrial quality control, further compromise mitochondrial function. Overall, mitochondrial dysfunction is linked to neuronal death, contributing to Parkinson's disease progression and severity.

In many neurodegenerative diseases, including Parkinson’s disease, there are problems with autophagy. Autophagy is the process by which cells “digest” or break down damaged or old cell components, ranging from proteins to cell organelles like mitochondria.

You can look at autophagy as the incinerators cells use to get rid of waste materials, and to recycle their components.

Reduced autophagy leads to accumulation of proteins, like alpha-synuclein, which plays an important role in Parkinson’s disease, as explained here.

Reduced autophagy also leads to accumulation of damaged or old cell components, like mitochondria.

Various companies are developing methods to improve autophagy, or reduce protein accumulation. This can be done in various ways:

- Using antibodies. Antibodies are proteins that can bind to the protein that accumulates, like alpha-synuclein. These antibodies attach to the proteins, and cause the breakdown of these proteins by the immune system. The immune system also uses antibodies to attach to and attack viruses and bacteria.

- Methods to improve lysosomal function. The lysosomes are important cell components. These are little vesicles that break down waste or damaged molecules and components of the cell.

- Tagging alpha-synuclein so they are broken down (transported to the lysosomes).

Below you can find examples of therapies and companies that use this and other methods to reduce the accumulation of protein in the brain.

Alpha-synuclein therapies, particularly antibodies, aim to treat Parkinson's disease by targeting the abnormal accumulation of alpha-synuclein protein in the brain.

In Parkinson's, misfolded alpha-synuclein aggregates form toxic clumps (Lewy bodies), leading to neuronal damage and degeneration.

Antibodies designed to recognize and bind to these toxic forms of alpha-synuclein can help neutralize and clear them from the brain, reducing their spread and protecting healthy neurons.

By preventing further aggregation or aiding in the removal of existing clumps, these therapies may slow disease progression and alleviate symptoms related to motor and cognitive decline in Parkinson's disease.

Various companies are developing gene therapies for Parkinson’s disease. However, these approaches will be less effective for people with “sporadic”, non-genetic Parkinson’s disease.

Sporadic Parkinson’s disease is caused by many different mechanisms, risk factors and exposures. For example, mitochondrial dysfunction, oxidative stress, the microbiome and protein accumulation all seem to play a role in the origin of this disease.

So changing just one gene with a gene therapy will likely have little impact. Also, gene therapy is very expensive, and it remains to be seen if it will be approved by regulatory bodies.

Often, these companies use viral vectors or lipid nanoparticles (LNPs) to deliver a gene into cells.

Viral vectors are modified viruses that carry a gene and infect cells, thereboy introducing the gene into the cells. Examples are Adeno-Associated Viruses (AAVs).

LNPs are small vesicles that carry the gene and merge with cells, introducing the gene into the cells.

The gene is then expressed in the cells, meaning it contains the instructions to build a specific protein. This protein then can for example produce missing substances for the cell, or take over the function of a malfunctioning protein.

The gene in the viral vectors or LNPs can be encoded by DNA or RNA. For example, AAVs contain DNA encoding for a gene (protein). LNPs often contain RNA encoding for a gene (protein).

The microbiome likely plays an important role in Parkinson’s disease, as explained here.

Various companies are developing therapies to modify the microbiome to partially reverse or slow down Parkinson’s disease.

Treating oxidative and metabolic stress in Parkinson's disease can help slow disease progression and protect neurons.

In Parkinson's disease, oxidative stress results from an imbalance between reactive oxygen species (ROS) and the body's ability to neutralize them, leading to mitochondrial dysfunction and neuronal damage, especially in dopaminergic neurons.

Metabolic stress further exacerbates this by impairing energy production, critical for neuronal survival.

Therapeutic strategies aimed at enhancing antioxidant defences, improving mitochondrial function, and optimizing cellular metabolism could reduce oxidative damage, protect neurons, and ultimately slow the degeneration process in Parkinson's disease.

Slowing down or inhibiting inflammation can be a potentially promising strategy in treating Parkinson's disease by reducing neurodegeneration.

In Parkinson's disease, chronic inflammation driven by activated brain cells (microglia and astrocytes) leads to the release of pro-inflammatory cytokines that exacerbate neuronal damage, particularly in dopaminergic neurons.

This ongoing inflammatory response contributes to oxidative stress, mitochondrial dysfunction, and the accumulation of misfolded proteins, all of which accelerate neuron loss.
By targeting inflammatory pathways, such as blocking cytokines or modulating immune cell activity, therapies can potentially protect neurons, slow disease progression, and improve motor and non-motor symptoms, enhancing overall patient outcomes.

Targeting leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease could mitigate its progression by inhibiting the overactive LRRK2 protein, which chemically modifies other proteins by potting phosphate groups on proteins.

Abnormal, overactive LLRK2 activity is implicated in abnormal cell signalling, inflammation, and neuron degeneration.

Reducing LRRK2 activity may protect dopaminergic neurons, slow neurodegeneration, and alleviate motor and non-motor symptoms of the disease.

GBA1 therapies target the enzyme glucocerebrosidase (GCase), encoded by the GBA1 gene, which is implicated in Parkinson's disease (PD).

Mutations in GBA1 lead to reduced GCase activity, resulting in toxic accumulation of specific lipids which are normally processed by glucocerebrosidase (GCase).

This accumulation of toxic lipids can lead to lysosomal dysfunction and the accumulation of α-synuclein, a protein which is normally broken down in the lysosomes, and which accumulates in Parkinson’s disease.

GCase enhancers aim to restore the enzyme's activity, improving the breakdown of harmful substances, reducing α-synuclein buildup, and promoting cellular health.

By targeting this metabolic pathway, these therapies hold promise in slowing disease progression and alleviating symptoms in patients with PD, particularly those with GBA1 mutations.

Improving dopamine metabolism in the brain is crucial for treating Parkinson’s disease, as the condition is characterised by the loss of dopamine-producing neurons in the substantia nigra.

However, most of these treatments do not address the root causes of Parkinson’s disease (such as protein accumulation, mitochondrial disease and others). They aim to increase dopamine levels or dopamine signalling (for example by stimulating dopamine receptors).

Such approaches mainly lead to symptomatic improvement, as dopamine plays a key role in regulating motor control, and its depletion leads to the hallmark symptoms of Parkinson’s disease, such as tremors, stiffness, and bradykinesia.

Enhancing dopamine metabolism can be achieved by increasing dopamine production, reducing its breakdown, or improving receptor sensitivity.

Therapies such as levodopa, dopamine agonists, and inhibitors of enzymes like monoamine oxidase B (MAO-B) help maintain dopamine levels, alleviate symptoms, and improve patients' quality of life.

1. Red and infrared light therapy (neurobiomodulation)

Red and infrared light of specific wavelengths (namely 630-660 nanometer and 830-850 nm) can impact brain health, and can be helpful for Parkinson’s disease too.

The red light (630-660 nanometer) can increase blood flow, and infrared light (830-850 nm) can penetrate the skull and brain tissues.

(Infra)red light is absorbed by specific proteins inside the mitochondria, which improves mitochondrial function. Cells also react to the light by secreting healthy and repair molecules.

2. Epidural electrical stimulation

This device stimulates the spinal cord (R). It has been shown to improve freezing-of-gait in Parkinson’s patients, and other problems with gait and maintaining posture. It works by stimulating nerves in the spinal cord.

Here we describe start-ups, companies and research groups that are developing other approaches to Parkinson’s disease from the ones already mentioned on this page.