Parkinson’s disease and dementia with Lewy bodies are both characterized by impaired brain function tied to neural death. A landmark new study has identified how a main culprit behind neuron damage — the alpha-synuclein protein — harms the neurons.
Parkinson’s disease is a neurodegenerative condition characterized by impaired motor function and sense of physical balance.
Its symptoms stem from brain cell damage and death, also a feature of the neurodegenerative disease dementia with Lewy bodies (DLB).
DLB features both the impaired motor function of Parkinson’s, and the memory loss and other types of cognitive decline characteristic of Alzheimer’s disease.
People with Parkinson’s disease may also develop a form of dementia called “Parkinson’s disease dementia.”
In all of these diseases, the misfolding — faulty structuring — of a protein called “alpha-synuclein” leads to the formation of deposits that interfere with the healthy functioning of brain cells.
Typically, these form in neurons found in the hippocampus, the brain region that plays a key role in learning processes, and memory formation and recall.
Although it is known that misfolded alpha-synuclein protein aggregates eventually lead to brain cell death, and thus to the heavy impairment of various cognitive functions, so far, researchers have not understood the underlying mechanisms that lead to this outcome.
In a new study, senior researcher Laura Volpicelli-Daley — who works in the University of Alabama at Birmingham School of Medicine — and colleagues have decided to search for that missing insight.
Their paper — which is now published in the journal Acta Neuropathologica Communications — explains what changes take place at cellular level in the brain, after the formation of alpha-synuclein aggregates, and before neural death.
Volpicelli-Daley and her colleagues are hopeful that their findings may eventually lead to improved treatments that may prevent, or even help to reverse, neural damage likely to lead to dementia.
“In Parkinson’s disease, you can give levodopa to improve motor function; but there is nothing to stop the non-motor symptoms,” Volpicelli-Daley explains.
In a previous study, Volpicelli-Daley and her team at that time developed an experimental model of artificial alpha-sinuclein deposits in vitro, which allowed them to simulate the development of these aggregates in brain cells.
For the purpose of the new research, the scientists applied this technique to obtain alpha-sinuclein aggregates, which they then introduced to the brain cells of mice.
Then, they studied the changes that occurred in hippocampal neurons at the 7-day mark — a point at which brain cell death will not yet have been triggered.
At that stage, there were high levels of alpha-synuclein in the brain cells’ axons, the projections tasked with sending electrical impulses that carry information between neurons.
What Volpicelli-Daley and colleagues found was that alpha-synuclein aggregates led to strange faults within the hippocampal neurons’ “communication mechanisms.”
Thus, there was abnormal activity both at the presynaptic (signal-transmitting) and postsynaptic (signal-receiving) terminals of brain cells. And these changes occurred some time before neurodegeneration, followed by cell death, was triggered.
“Something is clearly going on with the neurons before they die,” notes Volpicelli-Daley, adding, “There is increased activity at the presynaptic terminal, the site of the neuron that releases chemicals called neurotransmitters.”
“On the other hand,” she continues, “there is decreased activity post-synaptically, the site of the neighboring neuron where these released chemicals activate messenger systems,” which “may suggest that there is plasticity in the neurons, that is, the neurons are adapting to the increased activity.”
This is not a good sign, since, “Over time, this abnormal activity may eventually lead to neuron death,” as Volpicelli-Daley explains.
The researchers’ work does not end with these discoveries, however. The senior author notes that more research should be done concerning the (still mysterious) alpha-synuclein itself, and the role it typically plays in the functioning of brain cells.
“The next step,” says Volpicelli-Daley, “will be looking at how alpha-synuclein increases presynaptic activity and whether this is a loss of alpha-synuclein function in this neuron compartment or it is caused by formation of toxic alpha-synuclein aggregates.”
Jeremy Herskowitz, who is the other senior researcher in this study, suggests that the team’s work constitutes a new landmark in the landscape of Parkinson’s disease and dementia research.
“This is a groundbreaking study and one of the first to address critical and previously elusive questions regarding how toxic alpha-synuclein affects the structure and physiology of memory neurons.”