Parkinson's Disease: Progress in Small Steps

Parkinson’s disease is the second most common neurodegenerative disease in the world, affecting over 1.5% of people over the age of 65. According to projections, its prevalence is expected to double by 2030. However, it can also affect individuals as young as 40, and currently there is no cure. At least not yet.

What is Parkinson's Disease?

Parkinson's disease was first described by James Parkinson in 1817. It is a complex and multisystemic neurodegenerative disease with both neurological and non-motor manifestations. It is progressive , and different phases have been described based on functional impairments.

The first phase, known as the early phase, features unilateral (one side of the body) symptoms, whether or not they lead to disability. The second phase, known as the complicated phase, "involves bilateral progression of the disease, with the patients either being able to tend for themselves (autonomous), or having more severe disabilities. The final phase, known as the late phase, sees patients losing their independence, often confined to wheelchairs or bedridden.

While less than 10% of cases are attributed to genetics, various factors such as age and environmental factors (heavy metals, air pollution, etc.) play a crucial role in the etiology of Parkinson's disease. The key characteristics at the time of diagnosis include severity of neuron degeneration producing dopamine (a brain substance necessary for controlling movement), along with accumulations of various proteins, some of which are known as "Lewy bodies" within surviving neurons.

Parkinson's disease affects the neural cells that produce dopamine in the ventral mesencephalon.

Location of the mesencephalon in the brain. (Source: neuromedia.ca)

All the symptoms of Parkinson's disease are linked to motor dysfunctions: reduced motor activity, resting tremors, difficulty initiating or stopping movement, muscle rigidity, postural reflex disorders (leading to loss of balance and falls), and facial issues. Walking and balance problems are present in the early stages of the disease and worsen with its progression. Frequent falls are a key stage in the progression of Parkinson's disease and a major cause of mortality in its later stages. Typically, a Parkinson's patient's gait is characterized by small shuffling steps, reducing walking speed, which becomes more jerky, with hesitant starts and stops. Turns are taken with a multitude of small steps, the head and torso turning as one. The posture becomes bent forward, with less swinging of the arms. Additionally, Parkinson's disease also causes depression, constipation, and dementia.

The Main Symptoms of Parkinson's Disease and Their Brain Origins (source: parkinsoninfo.org)

Current Treatments

There is currently no cure for Parkinson's disease. However, there are treatments that can slow the progression of symptoms:

Dopaminergic therapy: this involves taking tablets of a molecule called levodopa, a dopamine precursor to compensate for the reduced dopamine production in the brain. Walking difficulties and postural instability respond to this treatment, even in advanced stages, but less so than slowness of movement and muscle rigidity.

Deep brain stimulation: This involves placing small electrodes in strategic areas of the brain. These electrodes send a weak electrical current that blocks the signals responsible for motor symptoms. Stimulation of certain brain areas can be effective in managing motor fluctuations, movement difficulties, tremors, muscle rigidity, and can improve walking and postural stability.

Cholinesterase inhibitors: Cholinesterase "...is a protein that repurposes certain molecules, such as acetylcholine into a form usable by our receptors in the brain. These treatments are used to reduce the dementia associated with Parkinson's or Lewy body disease. They also appear to reduce falls and improve walking, but further studies are needed to confirm the results.

Methylphenidate treatment: This molecule blocks the reuptake of dopamine and norepinephrine in the striatum and prefrontal cortex. It can be used as a treatment option alongside deep brain stimulation in advanced stages to improve walking.

Physical exercises: Physical activity has a protective role on neurons and slows the progression of the disease by boosting dopamine production. It is generally recommended to engage in physical activity for at least one hour three times a week, especially so in the case of Parkinson’s disease. Walking and endurance exercises improve walking, balance, and cognitive issues. Activities like dancing, especially in pairs, tai chi, or aerobics improve balance, mobility, and muscle strength, reducing the number of falls in the short and long term. Table tennis reduces tremors and stiffness. Intensive and multidisciplinary functional rehabilitation programs, such as SIROCCO, improve patients' quality of life up to a year after the program.

A Disease originating in the gut?

In addition to typical motor disturbances, Parkinson's patients also suffer from various non-motor manifestations, such as constipation. The hypothesis, supported by several studies, suggests that the disease may start in the gut and gradually progress to the brain. However, there appear to be two types of Parkinson's disease: one that starts in the brain and does not necessarily present gut microbiota disorders and another in which symptoms begin in the intestines.

The causes of intestinal issues in Parkinson's patients are not clear, but recent research has shown that intestinal dysbiosis, or an imbalance in the gut microbiota, is prevalent among Parkinson's patients and may be linked to motor symptoms. A higher presence of Desulfovibrio bacteria has been found in Parkinson's patients, and the quantity of these bacteria is related to the severity of symptoms.

Studies have shown that the gut microbiota may regulate mitochondrial metabolism and inflammation by interacting with the mitochondria (which provide energy to cells): intestinal AMPK enzymes (metabolic detectors of the cell allowing it to adapt to changes in its environment and protect energy resources), modulated by the gut microbiota, interact with the cell’s stress signalling pathways. However, how the gut microbiota affects the brain remains unclear. The loss of integrity of the blood-brain barrier, particularly due to the loss of pericytes (contractile cells surrounding capillaries to various extents), could contribute to the passage of substances from the intestine to the brain and lead to neuronal damage.

Fecal Microbiota Transplantation in a Mouse Model

Numerous recent studies have suggested that alterations in the gut microbiota play a role in modulating neuronal inflammation in Parkinson's disease. Additionally, mitochondria have been reported to play a crucial role in modulating immune responses, connecting neuronal degeneration and neuronal inflammation. Researchers have conducted fecal microbiota transplants from Parkinson's patients and healthy subjects into mice with induced Parkinson's disease. Transplanting fecal matter from a Parkinson's patient to a mouse exacerbates the neurotoxicity of the induction in the mouse, inhibiting the AMPK/SOD2 signaling pathway and worsening gut dysbiosis, while transplanting fecal matter from healthy subjects alleviates neurotoxicity by positively regulating the AMPK/SOD2 pathway and adjusting gut dysbiosis. Inducing Parkinson's disease in mice leads to the loss of nigrostriatal pericytes, but transplanting human fecal matter controls and partially prevents this loss.

The results suggest that the gut microbiota of control subjects can regulate mitochondrial oxidation resistance in neuroinflammation and reduce the loss of nigrostriatal pericytes and disruption of the blood-brain barrier mediated by the induction of Parkinson's disease in mouse models.

Hope for a New Treatment

Further studies are needed to better understand the specific bacteria or metabolites that contribute to neurodegeneration and elucidate their functions in Parkinson's disease. To date, fecal microbiota transplantation is only used in the therapy of recurrent Clostridioides difficile infections, indicating that the technique already exists. Other avenues are also being explored, including links between neuronal inflammation and immunity, or the role of the endoplasmic reticulum in neurodegeneration. Progress is being made in small steps, offering real hope.

Steps Towards Other Diseases

Research at the Pasteur Institute suggests that protein aggregates formed in Parkinson's disease may use microtunnels to spread to other neurons and propagate the disease, or to other types of cells to halt the disease (particularly microglial cells, which are part of the brain's immune system). In parallel, these other cells that destroy protein aggregates would send healthy material (such as mitochondria, which provide energy to cells) to diseased cells. Protein aggregates in neurons are responsible for other neurodegenerative diseases, such as Huntington's chorea (aggregation of huntingtin) or the more well-known Alzheimer's disease (amyloid beta peptide plaques).

Although these recent studies are in their early stages, but we are slowly heading toward a cure for these diseases.

Sources :

1. Chakraborty R. et al. Tunnelling nanotubes between neuronal and microglial cells allow bi-directional transfer of α-Synuclein and mitochondria. Cell Death & Disease. 2023.
2. HCL [En ligne] Lyon : SIROCCO : programme de rééducation intensive, multidisciplinaire chez des personnes atteintes de la maladie de Parkinson. Publié le 15/04/2022, Cité le 25/09/2023. https://www.chu-lyon.fr/sirocco-programme-de-reeducation-intensive-parkinson
3. Inoue K. et al. Table tennis for patients with Parkinsin’s disease : A single-center, prospective pilot study. Clinical Parkinsonism & Related Dirorders. 2021.
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