Molecular Medicine Israel

Novel Cellular Pathway Identified for Early-Onset Dementia

Neurodegenerative diseases are often misdiagnosed due to overlapping symptoms, the lack of specific tests, and deficiencies in understanding the underlying pathogenesis of the disorders. However, researchers at the University of York believe they have uncovered a new mechanism that potentially drives the progression of a particularly aggressive form of dementia.

The scientists knew that mutations within genes for endosomal trafficking had been previously linked to frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. Using a genetic screen for the enhancement of the FTD phenotype, the scientists found a strong association with a mutation in the endosomal sorting complex subunit CHMP2B.

The findings from this study were published online today in the Journal of Cell Biology through an article entitled “Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia.”

FTD is one of the most common forms of early onset dementia that typically manifests within patients in their fifties. As the name suggests, the disease typically affects the frontal and temporal lobes of the brain, areas generally associated with language, personality, and behavior. Trying to better understand the mechanisms for why these brain regions experience early neuronal loss is what drove the University of York scientists.

“These findings shed light on the events occurring in neurons as dementia takes hold. The more we know about the steps that occur in disease progression, the more opportunities we have to intervene with potential therapies,” stated Sean Sweeney, Ph.D., lecturer in the department of biology at the University of York and senior author on the study.

Dr. Sweeney and his team used Drosophila neurons to uncover cellular events occurring at the neuronal synapse. The team found that neurons harboring mutations in the small GTPase Rab8 potentiated synaptic overgrowth and cell death they observed with the CHMP2B mutants. However, the mutant phenotype could be rescued through the overexpression of wild-type Rab8.

”We hope that this work helps to tease apart complex molecular processes occurring in neurons and identify how these can go wrong in neurodegenerative diseases, such as frontotemporal dementia,” said Ryan West, Ph.D., research scientist in Dr. Sweeney’s laboratory and lead author on the study.

Dr. West found that disruptions in vesicular trafficking and endosome recycling led to the activation of signaling pathways that stimulated synaptic growth. Drs. West and Sweeney believe that these same pathways are involved in the promotion of neurodegeneration and are focusing their current efforts to identify additional genes that may be involved in the process.

“We know less about the underlying causes of frontotemporal dementia than some other kinds of dementia, so research like this is a vital step towards developing treatments for the condition. Further research will be needed to determine whether this mechanism plays a similar role in humans,” explained Clare Walton, Ph.D., research communications manager at Alzheimer’s Society, which helped fund the current research.

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