Tau Protein Levels May Be Useful Biomarkers of ALS Progression
Tau protein levels are unusually high in the motor cortex of amyotrophic lateral sclerosis (ALS) patients with a mutation in the C9orf72 gene, a study reported.
The motor cortex, a part of the cerebral cortex responsible for the planning, control, and implementation of voluntary movement, is the brain region most affected in ALS.
Investigators at Massachusetts General Hospital also identified new ALS-specific mutations in the MAPT gene — which codes for tau — and demonstrated that the levels of specific tau proteins in patients’ cerebrospinal fluid can help to predict disease progression and might serve as a disease biomarker.
Their study, “Novel genetic variants in MAPT and alterations in tau phosphorylation in amyotrophic lateral sclerosis post-mortem motor cortex and cerebrospinal fluid,” was published in Brain Pathology.
Tau is a protein important for maintaining cellular structure, and shuttling molecular cargo to different parts of the cell. However, when tau becomes hyperphosphorylated — a kind of chemical modification involving the addition of many phosphate groups — it forms abnormal clumps or tangles in cells.
While such tau clumps are a hallmark of Alzheimer’s disease, recent evidence suggests that these protein tangles are also present in ALS, namely in the motor neurons that are progressively lost over the disease’s course.
“This study focused on tau, a protein that is critical for stabilizing the structure of nerve cells … and whether it plays a role in ALS pathogenesis [development] as it can form aggregates and lead to cellular dysfunction in a number of neurodegenerative disorders,” Ghazaleh Sadri-Vakili, PhD, the study’s senior author and director of the NeuroEpigenetics Laboratory at the MassGeneral Institute for Neurodegenerative Disease, said in a press release.
The scientists examined post-mortem brain tissue from 52 ALS patients and 25 people without a neurological disease (a control group) to investigate whether the levels of certain phosphorylated tau proteins differ with ALS and if mutations in the MAPT gene are specific to ALS.
Results showed that people with ALS and C9orf72 mutations had significantly higher levels of total tau proteins and of a phosphorylated form called pTau-S396 — meaning it has a phosphate chemical group on the serine (S) amino acid, one of the building blocks of proteins, in the position 396 of the protein.
Other phosphorylated forms — pTau-S404 and pTau-T181 — were not different between controls and C9orf72-ALS patients, although pTau-T181 was significantly lower in the overall ALS group (samples from patients with and without C9orf72 mutations).
“These findings highlight a differential pattern of phosphorylation at specific amino acid residues across tau protein in ALS,” the researchers wrote.
Using genetic data collected from thousands of ALS patients and controls, obtained from the ALS Knowledge Portal (ALSKP) and Project MinE, the researchers also identified 36 variants of the MAPT gene in a total of 42 patients.
Of them, 15 variants were unique to ALS, as they were not present in any of the more than 140,000 genetic samples collected globally. Eight of these variants were observed in the part of the gene responsible for dictating how tau binds to microtubules — a tube-like structure inside cells — potentially affecting tau clumping.
“We also identified new genetic mutations in the tau gene that are specific to ALS and may have functional consequences that may exacerbate disease onset or progression,” Sadri-Vakili said.
“It is likely that these eight variants observed in ALS cases explain or significantly contribute to neurodegeneration in these patients,” the researchers noted.
Working in samples of cerebrospinal fluid — the clear fluid that surrounds the brain and spinal cord — collected from the two databanks’ patients and controls at various times — the scientists then examined if tau levels and its phosphorylated forms in this fluid might predict ALS progression. Baseline (initial) tau levels were seen to correlate with pre-baseline disability progression on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores.
The ratio between pTau-T181 and total tau (pTau-T181:tau ratio) in baseline samples, however, associated with fewer pre-baseline changes in ALSFRS-R scores. In essence, people who were progressing more slowly before their initial tau measurements had a higher ratio of these two proteins.
These “data also provide additional support for the use of pTau-T181:tau ratio as a potential biomarker for ALS and highlight a potential role for pTau-T181 in ALS pathogenesis, given that CSF levels reflect the significant decrease in pTau-T181 across ALS,” the investigators wrote.
“These findings are exciting as there is an unmet and urgent need for disease biomarkers in ALS,” Sadri-Vakili added.