Given Proteins in Blood Cells May Be Markers of ALS and Its Likely Course

Levels of specific proteins found in specialized immune cells — white blood cells like lymphocytes and monocytes — can serve as biomarkers for amyotrophic lateral sclerosis (ALS), helping doctors to diagnose the disease and its likely progression, a study reported.

These specialized immune cells, called peripheral blood mononuclear cells, include key players in an immune response to a perceived threat, like types of T-cells, B-cells, and natural killer cells.

The study, “Diagnostic and prognostic values of PBMC proteins in amyotrophic lateral sclerosis,” was published in the journal Neurobiology of Disease.

ALS lacks validated biomarkers for early diagnosis or prognosis (a disease’s likely course), both important for getting a person onto treatment, monitoring the response to therapy, and tracking disease activity.

Neurofillaments are considered the most promising biomarker so far, but need to be measured in the cerebrospinal fluid (CSF, the liquid surrounding the brain and spinal cord), which is invasive. Their levels are also abnormally high in people with ALS and those with other neurodegenerative diseases.

Scientists have identified a group of proteins with biomarker potential in peripheral blood mononuclear cells (PBMCs), including  proteins involved in RNA stability and protein clumping, like the PPIA, HSC70, hnRNPA2B1 and TDP-43.

Of note, RNA is the “genetic template” that converts the information stored in DNA into proteins.

A lack of the protein PPIA, for instance, has been shown in studies to speed disease progression and protein aggregation in a mouse model of ALS. Unusually low levels of PPIA in peripheral blood mononuclear cells is also associated with early onset ALS.

However, PPIA’s value — and that of the other candidate proteins — in diagnosing or monitoring the disease, and so serving as biomarkers, has yet to be established.

Researchers in Italy set out to analyze protein levels in PBMCs in distinct groups of people: 93 ALS patients, and, as controls, 104 healthy individuals, and 111 adults with other central nervous system diseases, such as Parkinson’s and multiple sclerosis.

They extracted proteins from participants’ blood cells, and separated them into two components — soluble fractions (containing highly soluble proteins, or those that dissolve in a liquid, like proteins in a cell’s cytoplasm) and insoluble fractions (containing membrane proteins and other insoluble, or non-dissolving, proteins).

The team found that some proteins in the soluble and insoluble fractions were able to distinguish ALS patients from both control groups, and to predict patients’ likely rate of disease progression and disease course.

In particular, the best combination for distinguishing ALS patients from healthy controls were levels of soluble PPIA and insoluble hnRNPA2B1 together. Likewise, a combination of soluble PPIA, insoluble TDP-43, and soluble hnRNPA2B1 levels were able to best distinguish ALS patients from people with other CNS diseases.

When ALS patients were stratified based on rates of disease progression — fast, moderate or slowly progressing as measured using the ALS Functional Rating Scale Revised (ALSFRS-R) — a decrease in soluble hnRNPA2B1 and an increase in insoluble hnRNPA2B1 levels were seen as the rate of progression quickened.

The higher the level of insoluble hnRNPA2B1 and the lower that of soluble hnRNPA2B1, the more likely a person is to have greater rates of ALS progression, the researchers reported.

Finally, they examined possible connections between protein levels and clinical variables for ALS patients (i.e., disease severity, progression, duration of symptoms when blood taken, and disease duration).

They found that soluble PPIA had the potential to predict prognosis, as patients with high levels of soluble PPIA had a 8% lower risk of death than those with low levels of this form of the protein, after adjusting for other factors.

“In conclusion, PPIA is a disease modifier with prognostic potential,” researchers wrote. “PBMC proteins indicative of alterations in protein and RNA homeostasis [balance] are promising biomarkers of ALS, for diagnosis, prognosis and patient stratification.”