Lysosomal Dysfunction and the Death of Neurons via Ferroptosis

Here find supporting evidence for the SENS view of lipofuscin and lysosomal dysfunction in aging. Lysosomes are the recycling units of the cell, packed with enzymes to break down unwanted structures and molecules into raw materials. Over time, long-lived cells such as the neurons of the central nervous system are negatively affected by the build up of resilient metabolic waste that is challenging to break down. Collectively this waste is called lipofuscin, but it contains many different problem compounds, and overall is poorly catalogued. Lysosomes in old neurons are observed to be bloated and dysfunctional, leading to cells that become overtaken with broken machinery that cannot be recycled. As noted here, the end result is cell death, and an accelerated pace of neural cell death is the road to neurodegenerative conditions.

A toxic brew of lysosomal lipids, reactive iron atoms, and oxidative stress can spell doom for human neurons. This is the upshot of the first-ever CRISPR screens at the genome-wide level in these cells. Researchers used the genome-editing tool to dial up or down expression of each protein-coding gene in the human neuronal genome. They uncovered a surprising connection between endolysosomal processing and the iron-dependent cell-death pathway called ferroptosis.

Zeroing in on that pathway, the researchers found that in the absence of the lysosomal protein prosaposin (PSAP), glycosphingolipids accumulate in the lysosomes, setting off oxidative stress. This results in a toxic mesh of ferrous ions and peroxidized lipids that can kill neurons via the ferroptosis pathway. The findings connect pathways that have been implicated separately in neurodegenerative disease, and support the idea that iron-rich "aging pigments" of lipofuscin, commonly spotted in older brains, might not be so benign after all.

What is the connection between PSAP and ferroptosis? Examining PSAP knockout neurons, the researchers found that the lysosomes were dramatically enlarged, and chock-full of glycosphingolipids. Strikingly, they found that these lipid-logged organelles were also electron-dense, suggesting they were loaded with iron. In fact, these densities bore an uncanny resemblance to lipid-iron granules called lipofuscin, also known as aging pigment. Lipofuscin soaks up the metal ions from the detritus of iron-rich organelles such as mitochondria, and this iron is thought to provoke the production of reactive oxygen species via the Fenton reaction.

Could this cascade play out in the aging brain? All of the culprits are there. For one, oxidative stress is known to rise in the brain with age, and lysosomal function also flags. Levels of not only lipofuscin, but also reactive iron increase in aging brains and even more so in neurodegenerative disease.



So.... even if you had the exact enzymes you need to break down lipofuscin, how do you deliver those enzymes to the lysosomes?

Or can you just deliver the enzymes freely in tissues? The blood stream?

Posted by: greg schulte at April 16th, 2021 11:24 AM

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