TAUOPATHIES
Tau is a neuronal microtubule-associated initially soluble cytosolic protein that promotes microtubule polymerization and bundling and is responsible for microtubule stabilization and transport of proteins in axons. Abnormal forms of it are associated with neurodegeneration.
Intracellular neurofibrillary tangles mainly composed of insoluble hyperphosphorylated aggregated tau, is the hallmark of several neurodegenerative diseases collectively-termed tauopathies such as tau-related frontotemporal dementia (FTD-tau) and progressive supranuclear palsy (PSP).
Tau-Related Frontotemporal Dementia
Clinical features: FTD is a generally slowly progressive syndrome typically manifesting as either behavior disturbances or language deficits.
Epidemiology: Considered one of the most common cause of dementia under 60 years of age, FTD can also develop in older individuals. Occurrence is worldwide, with an estimated 30,000 affected individuals in the US.
Genetics: Most FTD is sporadic, but some is familial. Many cases of familial FTD are caused by known genetic factors, including mutations and other abnormalities in the gene producing the protein tau (FTD-tau). The most common genetic abnormalities are mutations in the gene C9orf72 and the gene producing the protein progranulin. In about 1/3 of the latter types of FTD, amyotrophic lateral sclerosis also occurs.
Neuropathology: In FTD-tau, dense aggregates of this protein are seen in the brain post-mortem; other findings exist for C9orf72 and progranulin FTD.
Diagnosis: The clinical presentation often overlaps with Alzheimer’s disease, so tests to exclude it may be performed. Genetic tests for known mutations are also often performed.
Progressive Supranuclear Palsy
Clinical Features: PSP affects multiple aspects of motor function, including eye movements and balance, as well as cognition. A particular type of eye movement (vertical gaze palsy) is common, as are falls; dementia develops as PSP progresses. Several clinical subtypes exist. Death usually occurs about 7 years after disease onset.
Epidemiology: Occurrence is worldwide; PSP affects about 20,000 people in the United States.
Genetics: The great majority of PSP is sporadic.
Neuropathology: Aggregates containing a particular type of tau (so-called “4-repeat” tau) in certain regions are almost always found in post-mortem brain examination.
Diagnosis: Diagnosing PSP, especially early, is challenging because clinical features overlap with Parkinson’s disease, which is much more common, and also with another rare condition (multiple system atrophy).
A possible genetic risk factor has been identified in three genome-wide association studies (GWAS), which causes increased production of tauC3. This suggests that targeting tauC3 may be beneficial for treatment of PSP.
