Molecular Mechanism of Parkinson’s Disease Revealed

The risk of developing Parkinson's disease has been closely associated with various genetic mutations. But the exact molecular mechanism contributing to the disease is unclear. A study at the University of Pennsylvania has revealed how two different variations in the function of an ion channel of lysosomes in the body contribute to play a crucial role in Parkinson's disease as published in the journal Nature.

Lysosomes are a type of cellular organelles responsible for the removal and recycling of a cells' waste. Ion channels are a type of proteins embedded in the plasma membrane (outer layer of a cell) to control crucial aspects of a cell’s physiology by the passage of ions inside or outside the channels.

It was seen that the variation that raises the risk of Parkinson's disease, is possessed by 17% of people and it causes a reduction in the function of an ion channel of lysosomes. Whereas variation that reduces the disease risk by 20% is present in 7% of the general population. This change enhances the activity of the same ion channel.

Molecular Driving Mechanism in Parkinson's Disease

Parkinson's disease is a progressive neurodegenerative disorder that primarily affects movement due to loss of nerve cells – neurons that produce a chemical messenger (neurotransmitter) in the brain called dopamine (black substance). It is characterized by the formation of inclusion proteins called Lewy bodies.

"We started with the basic biology, wanting to understand how these lysosomal channels are controlled. But here we found this clear connection with Parkinson's disease. To see that you can have a variation in an ion channel gene that can change the odds of developing Parkinson's both ways--increasing and decreasing it--is highly novel", says Dejian Ren, lead author and a professor in the School of Arts & Sciences' Department of Biology.

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A particular one membrane protein called TMEM175 was identified about 5 years back by Ren's group, which forms a channel allowing potassium ions to move in and out. Other studies using genome-wide association have also found two variations in TMEM175 that influences the risk of Parkinson's disease, either by turning it up or down.

Based on the observation that motor and cognitive impairments in Parkinson’s disease progresses more rapidly in those who carried one of the TMEM175 genetic variations, the team found that this potassium current mediated only through the channel – TMEM175, was activated by growth factors, proteins like insulin that respond to the presence of nutrients in the body.

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"When you starve a cell, this protein is not functional anymore. That was exciting to us because that tells us this is a major mechanism that can be used by the organelle to receive communications from the outside of the cell and maybe send communication back out", says, Ren.

Protein Channels and Neuronal Damage

Generally, all the protein channels acted upon by a specific (kinase) enzyme called AKT, is opened by the addition of a small molecule called a phosphate group. It was surprising to note that the TMEM175 opened with AKT simply by bypassing this step.

Another observation that the team had found was the mice model with the disease-risk-increasing mutation had a potassium current of just about 50% of that of normal mice, and in the absence of growth factors, the current was extinguished.

On the contrary, mice with the disease-risk-reducing mutation operated for several hours in the absence of growth factors, even longer than they did in normal mice, thereby pointing that the mutation in some way, is helping the mice to resist the effects of nutrient depletion.

The neuron cell culture that carried the mutation associated with more severe Parkinson's was also found to be susceptible to damage from toxins and nutrient depletion. Thus 17% of the population that carries this variation have more chance of neuronal damage when subjected to stressors.

Also, there was a striking increase in Lewy bodies within neurons when TMEM175 function declined, most likely due to the impairment in the function of lysosomes, which normally help digest and recycle waste generated by the cell.

Apart from these changes. the mice lacking TMEM175 showed a loss of a portion of the neurons that produce the neurotransmitter dopamine thereby resulting worse on coordination tests than normal mice.

These evidences may help formulate potential target for a drug that could slow the Parkinson's disease's progression.

Thus the compiled study not only highlights the molecular impairments involved in Parkinson's but also in other neurodegenerative diseases, particularly those related to lysosomes, which include several rare but very severe conditions.

Source-Medindia