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Jan 15

Research Bit: Selective vulnerability to TDP-43 diseases: contributions from the lysosome

Research Bits
The Packard Center welcomed Aimee Kao, MD, PhD from the University of California, San Francisco to a recent Investigator's meeting.

Meeting Date: 15 January 2021

Presenter: Aimee Kao, MD, PhD

Talk Title: Selective vulnerability to TDP-43 diseases: contributions from the lysosome


What was the question being asked?

How is the function of the lysosome related to the breakdown of protein homeostasis that’s observed in many neurodegenerative diseases?

Why is this important for ALS research?

The lysosome is a grouping of compartments throughout the cell that deal with the degradation of old, damaged, or otherwise unneeded materials, much like a garbage collector. The lysosome is quite selective about what it degrades, although this selectivity is often lost in the case of neurodegenerative diseases, such as ALS. Indeed, when the lysosome does not function properly, it can lead to the accumulation of proteins such as TDP-43, which may lead to significant issues in motor neurons. Using a C. elegans (nematode) model, Dr. Kao’s work focuses on the normal regulation of lysosome activity, as well as how this goes awry when neurons become diseased.

What was the take-home message?

Granulins, the chopped-up pieces of protein that remain once the lysosome processes a protein called “progranulin”, accumulate in cells throughout their lifetime. This accumulation seems to “gunk up” the lysosome, reducing its normal function as time passes. This observation provides crucial insight into how diminishing lysosome activity in older neurons may contribute to their death in the case of ALS.

How do you think the results of this study might impact future approaches to the treatment of ALS?

Now that we have an explanation for why lysosomes lose their ability to degrade cellular “garbage” as cells age, we can investigate how to reverse this process and prevent the accumulation of old and potentially toxic materials such as TDP-43.

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