The general mechanism of Parkinson's disease and ALS

Neurons and mitochondrial quality control

LifeSciencesToday based on materials from Harvard Medical School: Damage Control. Researchers connect pathway linked to Parkinson’s disease with genes mutated in ALS

In order for a cell to live, diseased or damaged mitochondria – its "energy stations" - must be removed from it. In the brain, control over the quality of mitochondria is so important that neurodegenerative diseases can be considered as a result of the accumulation of defective mitochondria in neurons.

Damaged and healthy mitochondria. (Photo: National Institute on Aging)

Scientists from Harvard University Medical School have linked this pathway, already associated with Parkinson's disease, with proteins mutating in amyotrophic lateral sclerosis – a lesion of motor neurons, also known as Lou Gehrig's disease. The results of their study are published in the journal Molecular Cell (Heo et al., The PINK1-PARKIN Mitochondrial Ubiquitylation Pathway Drives a Program of OPTN/NDP52 Recruitment and TBK1 Activation to Promote Mitophagy).

In healthy cells, damaged mitochondria are destroyed and disposed of through a process called selective autophagy. Translated from Greek, this term means "self-eating". In recent years, the subject of intensive research by many laboratories around the world has been the question of how the labeling of mitochondria "sentenced" to disposal occurs.

Proteins associated with Parkinson's disease

Damage to mitochondria triggers the activation of two proteins, PARKIN and PINK1, marking their surface with chains of ubiquitin, a molecule signaling the cell to get rid of these defective organelles. The fact that these proteins are the culprits of the early onset familial form of Parkinson's disease has been known for more than a decade, but their role in controlling the quality of mitochondria has only recently been clarified. And how cells recognize signals about the need for recycling and which proteins, after recognition, take part in this process, scientists study and for a very short time.

The first key ideas about these underlying mechanisms were presented several years ago, when it was discovered that the OPTN autophagy receptor protein, together with the TBK1 protein kinase, participates in the removal of pathogenic bacteria from cells through autophagy. Interestingly, both of these proteins – OPTN and TBK1 – mutate in amyotrophic lateral sclerosis (ALS), but what contribution they make to the development of this neurodegenerative disease remained unclear.

A group of scientists led by Wade Harper mechanistically linked these two sets of proteins and described a multi-stage way to control the quality of mitochondria. The PARKIN and PINK1 proteins at the origin of the cascade of reactions function at the beginning of the mitochondrial utilization process, binding ubiquitin chains to defective mitochondria, while the OPTN and TBK1 proteins acting later bind to these ubiquitin chains, making damaged mitochondria targets of the autophagy mechanism.

It is important to note that the binding of the OPTN-TBK1 complex to ubiquitin chains stimulates the activation of TBK1 and the subsequent activation of the ubiquitin-binding function of OPTN, creating a self-reinforcing mechanism that is essential for the final delivery of mitochondria to the autophagosome.

Communication with the BASS

With the help of state-of-the-art quantitative mass spectrometry, genome editing and visualization, American scientists have obtained a detailed picture of how these two molecular pathways interact, and were able to form an idea of how they can link these two neurodegenerative diseases.

Diagram from an article in Molecular Cell

"For the first time, we were able to show how ubiquitination of damaged mitochondria activates their removal. This suggests that potentially a violation of the mitophagy process may contribute to the development of both ALS and Parkinson's disease," Harper, professor of molecular pathology and head of the Department of Cell Biology at Harvard Medical School, comments on the results of the study.

A postdoctoral fellow in his laboratory, Alban Ordureau, co-author of the article, had previously studied the biochemical interaction of PARKIN and PINK1 in the process of specific labeling of damaged mitochondria with ubiquitin.

"Here we are talking about how already ubiquitinated mitochondria are recognized by the cell and how the cell then gets rid of them with the help of proteins involved in the development of two different neurodegenerative diseases," explains Dr. Ordureau.

The lead author of the article Jin-Mi Heo, also a postdoctoral fellow at Harper's Laboratory, discovered that the TBK1 protein is activated when mitochondria are damaged by binding of the ubiquitin chain with the OPTN protein.

Stress and sensitivity

"If one pathway is stressed in a cell, disturbances in other pathways may occur," explains Dr. Heo. "Perhaps that is why we see similar characteristic signs in various diseases arising from different causes."

In Parkinson's disease, neurons producing the neurotransmitter dopamine are damaged, and in ALS, the function of motor neurons is impaired.

"There are very complex interactions between different mutations predisposing to the development of diseases, and [it matters] in which types of cells they act," adds Professor Harper. "Depending on the type of cells, one or another disease develops."

One idea is that different types of neurons exhibit different sensitivity to toxic proteins or toxic organelles–such as defective mitochondria. Motor neurons, for example, are much longer than most brain neurons; therefore, they may be more sensitive to the accumulation of certain types of toxic proteins or organelles than other types of neurons, Harper continues. Mutations in certain diseases may reflect sensitivity to different types of autophagosome cargo. The result will be the defeat of motor neurons in ALS and dopaminergic neurons in Parkinson's disease.

"What's amazing is that the Parkinson's disease genes act above the pathway mutated in motor neuron disease," Harper says. "So we have a genetic sensitivity in this pathway that should be different in different cells."

It may turn out that this is a common mechanism used by cells to get rid of a variety of damaged material in different types of neurons.

"We are starting to clarify this issue," Professor Harper shares his plans.

Portal "Eternal youth" http://vechnayamolodost.ru 02.03.2016