The number of dopamine-producing (dopaminergic) neurons at birth could influence a person’s lifetime risk of developing Parkinson’s disease, according to a group of experts.
Because these nerve cells die over the course of the disease, having fewer of them to begin with could translate to a higher risk, the scientists said.
Their report, “Does Developmental Variability in the Number of Midbrain Dopamine Neurons Affect Individual Risk for Sporadic Parkinson’s Disease?” is a review of scientific literature on the topic. It was published in the Journal of Parkinson’s Disease.
Parkinson’s is a progressive neurodegenerative disease, meaning that it steadily worsens as neurons die over time. The hallmark of Parkinson’s is the loss of dopamine — a neurotransmitter crucial for coordinating movement and regulating mood — that occurs when dopaminergic neurons in a brain structure called the substantia nigra malfunction and die.
The substantia nigra communicates with a neighboring brain structure called the striatum and it is believed that the loss of dopamine and dopaminergic neurons in these structures must cross a certain threshold before the symptoms of Parkinson’s become noticeable. The number of dopaminergic neurons an individual is born with, therefore, might influence how soon this threshold is reached.
Precisely how many of these neurons must die before symptoms appear remains an open question. No datasets of nigral (belonging to the substantia nigra) dopaminergic neuron counts are available for individuals with recent onset of Parkinson’s symptoms.
Nor is there a strong scientific consensus regarding the number of dopaminergic neurons in normal substantia nigra. Different methods for marking both dopaminergic neurons and age-related changes that can limit the number of functional neurons within the brain hinder precise counts.
To estimate the variation in dopaminergic neuron numbers across people, a team of scientists now examined the data in four previous studies. Each study followed strict exclusion criteria, such as not admitting patients with histories of neuropsychiatric disease and/or other neurological damage.
The studies are: Ageing of substantia nigra in humans: cell loss may be compensated by hypertrophy, published in 2002; The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson’s disease estimated with an unbiased stereological method, published in 1991; Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing, published in 2002; and Morphometry of the human substantia nigra in ageing and Parkinson’s disease, published in 2008.
In the review, the researchers focused on individuals who died before their 51st birthday, to minimize the risk that any observed variation was due to age-related effects, or to undiagnosed progressive disorders.
The studies showed a wide variation between individuals — ranging from 147% to 433% — in terms of the difference between those with the most and the fewest dopaminergic neurons. Such variation must be better understood to properly understand its significance, the researchers said.
Many of the genes implicated in rare developmental abnormalities in humans also are involved in determining the location, formation, and size of the dopaminergic neuron population. Based on past studies, the researchers suggest that subtle changes in how active these genes are throughout development likely determine the variation witnessed between individuals.
Although clearly defining these changes poses a significant challenge, some clues are emerging.
One recent study, for example, linked Parkinson’s risk to single nucleotide polymorphisms (SNPs) — changes of one single letter of the genetic code — that affected gene regulatory elements involved in early nervous system development. This, in turn, affects the number of neurons an organism has.
The alpha-synuclein protein plays a well-documented role in Parkinson’s progression. Its role in early development is less understood. One mouse study showed that the expression of the alpha-synuclein gene could affect the number of dopaminergic neurons in the substantia nigra. This suggests that, beyond the pathogenic role it plays in Parkinson’s, alpha-synuclein may help determine the early development and survival of dopaminergic neurons.
Non-genetic factors also appear to impact dopaminergic neurons by affecting critical periods of brain development. These factors include viral infection, exposure to environmental toxins, and hypoxia (low oxygen) at birth.
Based on the information collected throughout their review, the researchers propose that the number of nigral dopaminergic neurons individuals are born with and that survive immediately following birth affects their lifetime risk of developing Parkinson’s disease.
However, the researchers note that current knowledge of the factors influencing the development and survival of dopaminergic neurons is incomplete.
Therefore, “we need to explore the changes that occur both during development and during adulthood and aging when we seek to understand the full landscape of [Parkinson’s] risk,” they said.