Discovery of Protein Involved in TDP-43 Cytoplasmic Re-Localization Points to Potential Gene Therapy for ALS and FTD

A mouse stands on test tubes next to graphic of DNA double helix.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal and rapidly progress as neurodegenerative diseases. While inherited mutations can cause both conditions, they mostly appear sporadically in individuals without a known family history. Despite affecting different neurons, both diseases share a common hallmark: the pathogenic buildup of abnormal nuclear TAR-binding protein 43 (TDP-43) in the cytoplasm of affected motor neuron cells. Current theories propose that this cytoplasmic re-localization triggers toxic phosphorylation and fragmentation of TDP-43. Concurrently, a decrease of TDP-43 in the nucleus diminishes TDP-43-related physiological nuclear functions, contributing to the diseases’ progression (1).

Although this cytoplasmic accumulation of TDP-43 plays a significant role in the pathogenesis of ALS and FTD, the cellular mechanisms involved in the re-localization of TDP-43 to the cytoplasm is not known (2). A team of Australian neuroscientists led by Dr. Lars Ittner believe that they have found part of the answer for sporadic forms of the diseases. They identified novel interactions between pathogenic or dysfunctional forms of TDP-43 and the 14.3.3ɵ isoform of the cytoplasmic protein 14-3-3. By targeting this interaction with an AAV-based gene therapy vector, they were able to block and even partially reverse neurodegeneration in ALS/FTD mouse models.  

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Head Shots

When the 1996 Olympics were being held in Atlanta, I remember Muhammad Ali lighting the torch at the opening ceremonies, and how he shook from the Parkinson disease that devastated his body.

Since the 1920s, repetitive head trauma has been recognized as a cause of loss of neurological function in boxers, a condition originally called “dementia pugilistica”.

I confess; I am a fan of the gladiator sport that is American football. I enjoy cheering for “my” Green Bay Packers, and I have even been to a game at historic Lambeau field. But I was astounded (and disappointed) when the big concussion brouhaha started in the NFL a couple of years ago, and the NFL seemed surprised that head injuries were linked to long-term neurological issues (1).

The concussion discussion continues in the NFL this year with the recent decision by the NFL to enforce, more strictly, the existing rules against illegal hits that are “devastating blows” or “head shots” because of a bad weekend when multiple players were sidelined with injuries resulting from helmet-to-helmet or “devastating” hits (2).

It’s an important discussion, not because it affects the NFL and how the game of football is played, but because it gets attention and resources placed toward understanding repeat head injuries and their long-term consequences.

A recent study published in the Journal of Neuropathology and Experimental Neurology (3), takes a first step to understanding the long-term consequences of repetitive head injuries.

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