Early Changes in Molecular Pathway Impair Brain Cell Structure and Function in FTD/ALS

What is it about?

Deterioration of neuronal synapses (the connection between brain cells) leads to devastating loss of memory and movement in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The causes of this deterioration are unclear. However, our study found that an impairment in CREB, a protein crucial for keeping brain cells healthy and functional, occurs early in these diseases and contributes to synaptic loss. Importantly, we found that an imbalance in the enzyme that activates CREB (called PKA) is the main cause of CREB impairment. Using small molecule compounds to promote the activation of PKA, we saw normal CREB function restored to stop the deterioration of synapses.

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Photo by Bioscience Image Library by Fayette Reynolds on Unsplash

Photo by Bioscience Image Library by Fayette Reynolds on Unsplash

Why is it important?

Our findings, in both cultured brain cells and in the brain tissue of people with FTD/ALS, reveal the molecular defect that causes diminished CREB activity in FTD/ALS, driving the loss of neuronal connections and progressive cognitive and motor impairments. Understanding these mechanisms is a critical step to identify new therapies to stop the progression of these diseases. Our work puts a spotlight on the CREB pathway and suggests a potential treatment for FTD/ALS and other neurodegenerative diseases, including Alzheimer’s disease.