Targeting Multiple Pathological Proteins May Be Key to Treating Neurodegenerative Diseases

Proteinopathies, the misfolded proteins responsible for neuron deaths, have a claim to fame when it comes to rare neurodegenerative diseases. Their notoriety has made them the prime targets for disease treatments; however, they often co-exist with co-pathologies, making the often-used single-target therapies futile against the proteins’ varying degrees.

However, the call for more combination therapies has been made, thanks to a study published in Brain and conducted by researchers from Penn Medicine’s Center for Neurodegenerative Disease Research (CNDR). The team assessed protein pathologies present in patients with neurodegenerative diseases and found that those with more severe disease forms possessed more co-pathologies.

For their study, the researchers assessed 776 autopsied brains that included patients with rare neurodegenerative diseases, such as Pick’s disease, corticobasal degeneration (CBD), progressive supranuclear palsy, multiple system atrophy, frontotemporal lobar degeneration with TDP-43, and amyotrophic lateral sclerosis. They also looked at diseases such as Alzheimer's disease, Parkinson's disease with and without dementia, and dementia with Lewy bodies.

In the biopsies studied, researchers discovered co-pathologies to be common but varied among the many disease groups; the percentage of patients having co-pathologies ranged from 27% to 81%.

“Historically, the focus of most clinical trials has been on targeting the primary pathological proteins of a given neurodegenerative disease, but we see now that many of these disease-related aggregated proteins affect most older patients across a full spectrum of clinical and neuropathological presentations,” said senior author John Q. Trojanowski, MD, PhD, a professor of Pathology and Laboratory Medicine and director of Penn’s Institute on Aging, in a recent comment.

In addition, while tau, amyloid-beta (Aβ), alpha-synuclein (α-syn), and TDP-43 are the 4 primary proteins most commonly seen in nearly all major neurodegenerative diseases, the study showed that these diseases can and do have protein deposits aside from their most commonly known associations.

A prime example is evident in the CBD population evaluated in the study, which showed 52% of patients had multiple other neurodegenerative disease protein deposits present in addition to its primary protein, tau. At least 92% to 100% of patients were reported to have at least one form of tau.

After tau, Aβ followed as the next most common protein present in the neurodegenerative diseases studied with 20% to 57% of patients having a minimum of 1 type of protein deposit. TDP-43 deposits, which are characteristic pathological signatures of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, were the rarest, with only 0% to 16% of patients having the protein deposits. α-syn pathology, commonly seen in Parkinson’s disease, was also less common, with only 4% to 16% of patients having deposits.

“This gives us additional leverage to find ways to detect patients’ specific proteinopathies with increasingly sophisticated biomarker and imaging technologies,” Dr Trojanowski explained. “This will allow us, and other researchers, to better match participants with specific targeted therapies in clinical trials.”

The study also noted that the presence of multiple co-pathologies increased, which further support the previously established “proteopathic seeding” hypothesis conducted in model systems of neurodegenerative diseases. According to Penn Medicine, misfolded proteins may directly “cross-seed” other normal, vulnerable proteins to accumulate and clump via a cell-to-cell transfer of toxic proteins.

“Our study is an important first step in understanding the extent to which co-pathologies present in and impact all neurodegenerative diseases,” added co-author Virginia Man-Yee Lee, PhD, the CNDR director and a professor of Pathology and Laboratory Medicine. “Now, we need to probe these protein-to-protein interactions more closely to better understand how they progress in patients’ brains, with an eye toward clinical studies that combine targeted therapies to halt or slow accumulation of these disease proteins.”