Altered proteins in brain neurodegenerative diseases

Frontotemporal dementia associated biomarkers

The various FTD spectrum disorders are associated with brain accumulation of different proteins: tau, the transactive response DNA binding protein of 43 kDa (TDP43), or fused in sarcoma (FUS) protein, Ewing sarcoma protein and TATA-binding protein-associated factor 15 (TAF15) (the latter three are collectively known as FET proteins).

TAR DNA-binding protein of 43kDa (TDP-43)

TDP-43 is a major component of ubiquitin-positive inclusions that are one of the neuropathological hallmarks in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Only 50% of FTLD patients have aggregates positive for TDP-43. Unfortunately, TDP-43 in CSF originates mainly from blood. Measurements of TDP-43 in CSF and blood are of minor importance as a diagnostic tool, but may be important for monitoring therapy effects of TDP-43 modifying drugs in the future. 

FET/FUS proteinopathies

Recent reports identified mutations causative of neurological disorders in the genes encoding a family of RNA-binding proteins (RBPs) named FET. RNA-binding proteins (RBPs) are involved at all stages of RNA metabolism in neurodegenerative diseases. FET proteins are highly conserved and ubiquitously expressed. Recently, it has been suggested the involvement of FET proteins in neurological diseases, such as frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), where they have been found in cytoplasmic aggregates. Abnormal co-accumulation of FET proteins into pathological inclusions has been described in all subtypes of FTLD-FUS. FUS (fused in sarcoma) is the most examined protein; FUS is localized in dendritic granules and spines in neurons where it plays a role in mRNA transport into dendrites, which represents an essential process for local protein synthesis and synaptic plasticity. No CSF FET related-markers are available.

Additional biomarkers of any cause of neuronal damage or injury

Neurofilaments as marker of axonal injury

Neurofilaments are intracellular intermediate filaments found in the central and peripheral nervous systems. In neurons, they control axonal diameter, which is correlated with nerve conduction velocity. Neurofilament protein include three subunits: neurofilament light (NfL) chain of ~68 kDa, Nf medium chain of ~150 kDa, and Nf heavy chain of ~190– 210 kDa. After axonal injury, intracellular neurofilaments can leak into the extracellular space, leading to an increased concentration in the CSF. Comparable performance of NfL in blood and CSF demonstrates its promise as a noninvasive biomarker of neurodegeneration.

Astroglial biomarker

S100B protein is an astroglial 11 kDa calcium-binding protein. In the classic neurodegenerative disorders (AD, PD, ALS) S100B concentration in CSF usually reflects the severity of the pathological condition, whereas, in many cases, S100B levels in blood remains unchanged during the course of the disease. However, serum S100B is valuable in the assessment of mild head injuries.

Neuronal damage biomarker

Neuron specific enolase (NSE) is a glycolytic isoenzyme located in central and peripheral neurons and neuroendocrine cells. The measurement of NSE in CSF could be a sensitive index of neuronal damage. NSE is considered a biomarker of neuronal stress and has prognostic potential for a variety of neurological disorders. Serum NSE levels are significantly elevated in patients with unfavorable neurological outcome in a variety of conditions.

Inflammation in neurodegeneration

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein that is specifically expressed on microglia in the brain. TREM2 is one of the most crucial factors in regulating the innate immune system during AD progression. Soluble TREM2 (sTREM2) is the ectodomain released in a soluble form. sTREM2 is described to be a central regulator of microglial function and CSF sTREM2 is known to increase 5 years before the expected symptom onset in AD.