Parkinson's disease and autoimmunity
April 27, 2014
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in the world (the first most prevalent being Alzheimer's disease), affecting upwards of 7 million people. The characteristic symptoms of the disease include bradykinesia (slow movement), rigidity, tremor, and postural instability. The appearance of these symptoms corresponds with neurodegeneration, or the death of neurons, which occurs predominantly in a collection of nuclei in the brain called the basal ganglia.
The basal ganglia are found below the cerebral cortex and include the caudate and putamen (which together are often called the striatum), subthalamic nucleus, globus pallidus, and substantia nigra. These nuclei (another term for a cluster of neurons) work together to facilitate the execution of voluntary movements. While a movement signal doesn't generally originate in the basal ganglia, it seems that the basal ganglia get information about where we want to move from the cortex and then help make movement possible by doing things like inhibiting contradictory movements. The basal ganglia have a variety of functions, however, and are also thought to be involved in motivation, memory, and learning, among other things.
In PD, neurons in the substantia nigra are particularly affected. The substantia nigra (translated from Latin as "black substance") appears as a darkened area in the brainstem. The dark coloring is thought to be a result of neuromelanin, a pigment that in this case is found in dopaminergic neurons. The substantia nigra is one of the major areas of dopamine production in the brain. In PD, an individual may lose 50-70% of the dopamine neurons in this area by the time they die, and the progressive loss of these neurons is associated with a worsening of symptoms.
Why exactly that neurodegeneration occurs, however, is still unknown. A paper published recently in Nature Communications offers an explanation that may advance our understanding of the disease. The paper, written by Cebrian et al., examines the role of major histocompatibility complex (MHC) molecules in the pathophysiology of PD. The MHC is a collection of molecules found on the surface of cells; it tells the immune system whether the cell is healthy has been infected. If the MHC alerts the immune system to infection of a cell, cells like cytotoxic T cells may be summoned to destroy the infected cell.
It was thought for some time that neurons didn't express MHC, but recently a small number of studies have indicated that this view may not be correct. Cebrian et al. verified they could detect MHC-I (a particular class of MHC) in human postmortem brain samples, specifically in neurons in the substantia nigra and another nucleus called the locus coeruleus (a key site for norepinephrine production). They then found that they were able to induce the expression of MHC in human dopamine neurons derived from embryonic stem cells by exposing the neurons to an inflammatory substance commonly found in the blood and cerebrospinal fluid of Parkinson's patients. MHC expression also occurred in response to oxidative stress and exposure to the protein alpha-synuclein. During PD, alpha-synuclein clumps together in neurons to form pathological aggregations known as Lewy bodies.
Cebrian et al. also found that when neurons that expressed MHC were exposed to cytotoxic T cells, the T cells induced the death of the neurons. Thus, if human dopamine neurons are displaying MHC under conditions that occur in PD (like high levels of alpha-synuclein), then they may be open to attack from cytotoxic T cells. This could cause neurodegeneration through a mechanism that would suggest PD is an autoimmune disease.
But more research will be needed to make that conclusion. Although this study indicates it is plausible that autoimmunity is playing a role in PD, it is unclear whether this is really what is happening in those who have the disease. If autoimmunity is involved in PD neurodegeneration, then it certainly could also be involved in neurodegeneration associated with other diseases like Alzheimer's disease. Thus, understanding the contribution of autoimmunity to neurodegenerative disease pathophysiology could provide insight into some of the major causes of morbidity and mortality in the world.Cebrián C, Zucca FA, Mauri P, Steinbeck JA, Studer L, Scherzer CR, Kanter E, Budhu S, Mandelbaum J, Vonsattel JP, Zecca L, Loike JD, & Sulzer D (2014). MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nature communications, 5 PMID: 24736453