A service of Penn’s Neuroscience Graduate Group

There's a new janitor in town: cleaning up the mess in ALS

or, technically,
Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation [See the original abstract on PubMed]

Authors: Yvette C. Wong, Erika L.F. Holzbaur

Brief prepared by: Shachee Doshi and Patti Murphy
Brief approved by: Peter Dong
Section Chief: Shachee Doshi
Date posted: March 8, 2017
Brief in Brief (TL;DR)

What do we know: Mitochondria are machines in our cells that produce energy. When mitochondria get damaged, healthy cells break down the damaged mitochondria and throw them away. In neurodegenerative diseases like ALS (Lou Gehrig's disease), damaged mitochondria inside neurons are not broken down, and this might be one way in which neurons die.

What don’t we know: Why are damaged mitochondria not broken down inside neurons in people with neurodegenerative diseases? Can we find ways to help these people's neurons break down damaged mitochondria?

What this study shows: A protein called optineurin helps cells break down damaged mitochondria. When there isn't enough optineurin or the optineurin is abnormal (like it is in some cases of ALS), damaged mitochondria are no longer broken down and build up in the neuron.

What we can do in the future because of this study: We could design drugs to make optineurin even better at breaking down damaged mitochondria. These drugs would first be tested to see if they help animals with neurodegenerative diseases and then if they help humans with these diseases.

Why you should care: Neurodegenerative diseases (Alzheimer's Disease, ALS, Frontotemporal Dementia) cause a lot of pain to patients and their families and cost a lot of money to society as a whole. Damaged mitochondria are found in neurons of patients in all these diseases. Finding ways to help cells break down damaged mitochondria can help us treat patients with these diseases.

Brief for Non-Neuroscientists

Mitochondria are the energy powerhouses of the cell. They make the fuel for all the cellular machinery to run smoothly. Accumulation of damaged and dysfunctional mitochondria has been observed in many neurodegenerative diseases, including ALS, Alzheimer's disease and Parkinson's disease.

While it is unknown how mitochondria become damaged, it is known that accumulation of malfunctioning mitochondria is one of the factors contributing to neuronal cell death. Normally, a cell discards its damaged parts by a process known as autophagy. When it is mitochondria that are being discarded, this process is called mitophagy.

One reason damaged mitochondria might build up in neurodegenerative diseases is defective mitophagy. If there were a way to rescue this defect, it could help cells get rid of these damaged mitochondria. This study identifies a pathway to do just that. The authors find that a protein called optineurin can be recruited to the mitochondria, which in turn leads to the recruitment of autophagosomes. Autophagosomes are special structures that envelop and engulf damaged cellular material to degrade it. If optineurin is removed from the cell, autophagosomes are no longer recruited to damaged mitochondria. Adding normal optineurin back into the cell can rescue autophagosome recruitment, but adding back an altered (mutated) form of optineurin that is found in ALS cannot rescue autophagosome recruitment.

This study tells us that it may be possible to treat neurodegenerative diseases by increasing the amount of normal optineurin available in cells.

Brief for Neuroscientists

Mitochondrial dysfunction is a hallmark of many neurodegenerative diseases including ALS, frontotemporal dementia and Alzheimer's disease, and is implicated in disease pathophysiology. While mitophagy is a well-understood quality control mechanism that can degrade dysfunctional mitochondria, it seems to be compromised in these diseases. Optineurin is a protein that binds ubiquitin and the autophagosome via its LC3-binding domain, thus acting as an autophagy receptor. Mutations in optineurin have been found in familial cases of ALS. This paper describes a parkin-dependent role for optineurin in mitophagy in vitro. Using HeLa cells and confocal microscopy, the authors find that parkin is required to stabilize optineurin on the mitochondrial membrane, which in turn recruits the protein LC3 to initialize autophagosome formation. Depleting optineurin prevents autophagosome recruitment and mitochondrial turnover. This can be rescued by expressing wild type optineurin but not an ALS-linked mutant optineurin. Further, deleting autophagy receptor p62 did not prevent autophagosome formation, indicating a specific role for optineurin in initiating mitophagy. This study presents evidence for the contribution of mitochondrial dysfunction to cell death in neurodegeneration, and describes a mechanistic role for optineurin in mitophagy.

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