2023 Alzheimer's Association Research Fellowship (AARF)

Synaptic Proteome in Genetic Frontotemporal Lobar Degeneration

Can protein changes in structures used for brain cell communication predict the severity of Frontotemporal lobar dementia?

Rowan Saloner, Ph.D.
University of California, San Francisco
San Francisco, CA - United States

Background

Frontotemporal lobar dementia (FTLD) is one of a group of brain diseases characterized by the early onset of dementia (occurring by one's 40s or 50s) along with changes in personality, emotions and difficulty in comprehending language. FTLD impacts frontotemporal nerve cells, which exist in the front and side (temporal) regions of the brain. Studies suggest that brain changes associated with FTLD occur decades before clinical symptoms become evident. 

One of the earliest FTLD brain changes is a decline in the function of synapses, the specialized structures nerve cells use to send signals to one another to communicate. This decline may be linked to changes in synaptic proteins, especially among individuals with inherited genetic variations associated with FTLD. In initial studies, Dr. Rowan Saloner and colleagues have found that individuals with inherited FTLD have certain synaptic proteins in their cerebrospinal fluid (CSF, the biological fluid surrounding the brain and spinal cord) that may predict the severity of their disease. Greater knowledge of these proteins may help clarify how the disease progresses at its earliest stages.

Research Plan

Dr. Saloner and team will conduct an extensive study of synaptic CSF proteins in early FTLD. They will recruit 117 individuals with a genetic mutation for inherited FTLD and 47 individuals without the mutation. After acquiring CSF samples from these individuals, the researchers will use sophisticated analytical techniques to study the synaptic proteome (all the synaptic proteins) in the participants’ cerebrospinal fluid. Their analysis will identify novel groups (or “modules”) of proteins linked to inherited FTLD. Dr. Saloner’s team will also assess how these protein modules may be linked to various aspects of the disease, including brain shrinkage and synaptic dysfunction.   

Impact

Results from this study could shed new light on the mechanisms underlying synaptic dysfunction in FTLD They may also identify FTLD biological factors (or biomarkers) that can be targeted in early-stage disease therapies.