New microscopy in human tissues may lead to PET diagnosis of degenerative disease signatures

Anthony Fitzpatrick, Ph.D.

Columbia University

Funded in September, 2018: $200000 for 3 years
LAY SUMMARY .

LAY SUMMARY

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New microscopy in human tissues may lead to PET diagnosis of degenerative disease signatures

Investigators using a new microscopic technique in autopsy tissues from people with neurodegenerative diseases may be able to differentiate each disease’s molecular signature that could lead to diagnoses of patients through PET imaging.

Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, Amyotrophic Lateral Sclerosis, and Frontotemporal dementia all involve accumulations of pathological proteins in the brain. A different protein is involved in each disease, but in a similar process: the abnormal protein aggregates within nerve cell bodies, in the cells’ projections that receive and send messages, and in supportive nearby “glial” cells. The proteins form insoluble “amyloid filaments” (fibers) that cannot be degraded. The cells progressively die.  

These investigators hypothesize that amyloid filaments are not simply markers of disease, but drivers of selective neurodegeneration. Further, they hypothesize, the amyloid filament structure that is unique for each neurodegenerative disease constitutes a “signature” that can be identified using “cryo-electron microscopy (cryo-EM).” This technique, for which its original developers were awarded the 2017 Nobel Prize in chemistry, fires beams of electrons at proteins that have been frozen in solution to deduce the protein’s structure.

The investigators were recently able to visualize filaments of the abnormal protein “tau” that they extracted from the autopsied brain of a person who had Alzheimer’s disease (AD).  Now they will use this same process to extract and visualize filaments from autopsied brains of people who died from the other four degenerative diseases. They anticipate that cryo-EM’s resolution will be so strong that it can determine the basic structure of the amyloid fibril molecules in each disease. Then they will be able to derive key insights into how the filaments are formed, how they grow, how they initially are cleared from the brain, and how they form insoluble protein aggregates in the brain that lead to disease progression.

Moreover, if scientists can determine the molecular signature for each neurodegenerative disease, they will be in a position to develop PET tracers that bind to the molecules involved in each disease. PET then could be used to differentiate, diagnose, and monitor progression of each degenerative disease.    

Significance : This process may lead to development of PET imaging tracers to identify each neurodegenerative disease that clinicians can use to diagnose and to assess the effects of experimental therapies in slowing or preventing the toxic protein’s aggregation.