Considering Big tau as a novel and specific biomarker for spinal motor neuron pathology

Big tau is an isoform of tau that includes the large 4 A exon, resulting in an extended projection domain and an overall increase in apparent molecular weight from 40 to 65 kDa to 95-110 kDa. Its expression is highly restricted to the peripheral and autonomic nervous systems and select regions of the central nervous system. Although the precise function of Big tau remains unclear, we have proposed that the expanded projection domain of low molecular weight (LMW) tau by 250 amino acids of exon 4a and its structural properties may enhance axonal transport in long-projecting neurons and confer resistance to aggregation. Here, we propose a clinical perspective based on the properties of Big tau: the selective expression of Big tau in spinal motor neurons, but not in upper motor neurons or other spinal neuronal populations, is likely to make Big tau a specific biomarker for spinal motor neuron pathology. This expression pattern may be particularly valuable for tracking disease prognosis and progression in conditions such as amyotrophic lateral sclerosis (ALS) and related disorders, to identify when degeneration advances to lower motor neurons. Big tau could thus serve as a more specific biomarker to neurofilament or LMW tau proteins or can be used in combination with other biomarkers to enhance the specificity and sensitivity. This hypothesis can be readily tested using existing samples and assays applied to cerebrospinal fluid (CSF) and blood samples from patients. If validated through clinical studies, Big tau may provide clinicians with a new tool to better diagnose and monitor a variety of motor neuron degenerative disorders. To accelerate research in this area, I offer to share experimental data and an inventory of polyclonal antibodies specific to Big tau to the research community to enable further investigation of Big tau as a clinical biomarker.