• According to a recent study, Parkinson’s disease may result from a failure of neuronal cells’ normal house-cleaning function.
  • One of the hallmarks of Parkinson’s disease is a buildup of degraded proteins in brain synapses that may eventually create areas of dead neurons.
  • The study in Drosophila, fruit flies, found that a surge of calcium in healthy brain synapses initiates the cleaning process by triggering a protein responsible for cells that discard the debris.
  • However, when a gene mutation already associated with Parkinson’s is present, the protein does not respond properly to calcium’s signal, and synaptic cleanup fails to occur.

A gene mutation associated with Parkinson’s disease interrupts brain cells’ normal process for disposing of degraded proteins, according to a recent study. The result is a buildup of debris in synapses that may cause Parkinson’s symptoms.

In a study of Drosophila, fruit flies, researchers demonstrated that the release of calcium in neurons triggers autophagy — cell house-cleaning — and that the gene mutation inhibits this release.

Abnormal clumps of proteins called Lewy bodies, consisting primarily of clumps of the protein alpha-synuclein, are found in the synapses of people with Parkinson’s disease. Alpha-synuclein is normally involved in the cross-talk between brain cells. However, as misfolded alpha-synuclein proteins clump together, they kill neurons, leaving dead brain cells in their wake.

According to Biogen’s Dr. Warren D. Hirst, the hypothesis that a failure in autophagy results in Parkinson’s is not new. However, the new study documents, step-by-step, the possible players and mechanics behind autophagy’s failure. (Dr. Hirst was not involved in the study.)

The research is published in Neuron.

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Parkinson’s disease is the second-most frequently diagnosed neurodegenerative disease, following Alzheimer’s disease. There are nearly one million people in the United States living with Parkinson’s, and the number is expected to rise to 1.2 million by 2030. About 10 million people have Parkinson’s worldwide. Almost 90,000 new cases are diagnosed each year in the U.S.

In its advanced stages, critical dopamine-producing neurons in the brain’s basal ganglia die. This brain region controls movement.

The main symptoms of Parkinson’s are:

  • a tremor in the hands, head, arms, jaw, or legs
  • slow movement
  • stiff muscles that remain contracted for an extended period of time
  • impaired coordination and balance, with a potential for falling

Parkinson’s may also cause depression and other emotional changes, skin problems, urinary issues, constipation, and difficulty swallowing, chewing, and talking.

Most people diagnosed with Parkinson’s are over age 60, though about 5% may develop the disease earlier. It is not entirely clear the degree to which the disease may be inherited.

It’s important to note that the condition affects people differently — some may experience more severe symptoms such as losing all mobility, while others may continue to experience mild symptoms.

There is no cure for Parkinson’s disease, but treatment options such as medications, deep brain stimulation (DBS), and therapies, can help ease the symptoms.

Increasing evidence from existing research also suggests that a nutritious diet and regular exercise can help prevent and manage the condition and other neurodegenerative diseases such as Alzheimer’s.

A recent study found that just 6 minutes of high intensity exercise may help delay the onset of Parkinson’s and Alzheimer’s diseases by increasing the amount of neuroprotective brain-derived neurotrophic factor (BDNF) in the body.

Neurologist Dr. Santosh Kesari, who was also not involved in the study, described it as “a basic mechanistic paper taking a mutation that’s known to increase the risk of Parkinson’s, and testing what that mutation does in a fruit-fly model of Drosophila.”

The researchers found that in Drosophila, an influx of calcium at brain synapses was the initial indirect, initiator of autophagy.

They also determined that such synaptic calcium surges can be triggered by neuronal activity, or by starving cells of amino acids.

“The authors provide substantial evidence supporting a role for calcium in the initiation of autophagy within Drosophila synapses,” said Associate Professor of Neurology Ian Martin, also not involved in the study.

In particular, Asst. Prof. Martin noted, “The idea that synaptic autophagy could be coupled to neuronal activity, and that this autophagy is required for neuronal survival is generally well-supported in the study by an array of approaches, including biochemistry, genetics, synaptic physiology, and microscopy.”

Dr. Kesari described autophagy: “It’s the trash disposal for the cell.”

The study next demonstrated that the link between calcium and autophagy is a Parkinson’s-associated mutation in the protein Endophilin-A, abbreviated as “EndoA.”

EndoA is part of the endolysosomal system that other studies implicate as a potential early pathomechanism leading to alpha-synuclein clumps and Parkinson’s.

The calcium influx normally makes EndoA more flexible, making it available for the formation of the autophagosomes that drive autophagy.

The study found, however, that with the Parkinson’s-related mutation, the influx of calcium causes EndoA to stiffen, and this rigidity blocks the formation of autophagosomes, and therefore autophagy.

The new study is thus unique in two ways: its focus on autophagy specifically at synaptic terminals, and its demonstration that the Parkinson’s-related gene mutation blocks its initiation. Together, these insights advance the understanding of how the disease works.

Asst. Prof. Martin noted that the concept of autophagy failure playing a role in Parkinson’s is supported by findings from human post-mortem tissue. Beyond EndoA, pathogenic mutations in proteins such as alpha-synuclein and LRRK2 are also implicated in Parkinson’s.

“Genetic studies consistently point to a role for autophagy defects in Parkinson’s disease-related neurodegeneration.”

“We need to do the next level of work in human cells, and then ultimately, we need to think about how we can use this information to improve autophagy,” said Dr. Kesari.

How to do this, said Dr. Hirst, “is the key, $64 million, question. The field continues to search for autophagy enhancers. This continues to be challenging.”

As for the EndoA mutation itself, said Asst. Prof. Martin, “EndoA is not a good therapeutic target, and it’s not clear how treatments might try to rectify the loss of function caused by the mutation.”