Globular glial inclusions unveil enigmas of MAPT mutations
Neurodegenerative diseases are characterized by progressive dysfunction and loss of neurons leading to distinct involvement of functional systems defining clinical presentations 1. In the last two decades, proteins were placed in the centre of the pathogenesis of these disorders; thus, current molecular pathological classification of the most frequent adult‐onset neurodegenerative diseases is protein‐based 1. One of these proteins is tau, which is related to a group of disorders called tauopathies. The term primary tauopathy refers to disorders in which tau protein deposition is the predominant feature; the nomenclature overlaps with the classification of frontotemporal lobar degeneration (FTLD). Primary FTLD‐tauopathies are distinguished based on the ratio of 3 repeat (R)‐ and 4R‐tau isoforms, corresponding to two or three major phospho‐tau bands (60, 64 and 68 kDa) in western blot of sarkosyl‐insoluble fractions 2. Pick's disease (PiD) is a 3R tauopathy (60 and 64 kDa bands), while 4R tauopathies (64 and 68 kDa bands) comprise progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD) and globular glial tauopathy (GGT)2. Mixed 3R and 4R tauopathies (60, 64 and 68 kDa bands) include neurofibrillary tangle (NFT)‐predominant senile dementia, which overlaps with primary age‐related tauopathy, PART 3. There are different disease‐associated tau immunoreactive morphologies in neurons, in astrocytes and in oligodendroglia allowing the distinction of the neuropathological subtypes of primary FTLD‐tauopathies. Other than the various neuronal tau pathologies, the importance of astroglial tau‐deposition is exemplified by the distinguishing features of tufted astrocytes in PSP and astrocytic plaques in CBD, which abnormally accumulate tau in distinct cellular compartments 2. Oligodendroglial tau pathology received less attention and most of these inclusions have been described as coiled bodies. Following single case reports and small case studies, a consensus study defined a subgroup of primary tauopathies as GGT 4. Unfortunately, clinical phenotyping may not reliably predict underlying GGT as is true for other tauopathies 5. Importantly, the massive globular oligodendroglial cytoplasmic deposits are distinct from the coiled bodies seen in PSP, CBD or AGD. Their morphology is reminiscent of the α‐synuclein immunoreactive oligodendroglial cytoplasmic inclusions (Papp‐Lantos bodies) in multiple system atrophy, and in addition, they share further features such as white matter degeneration 6.
Mutations in the gene encoding tau (MAPT) have been associated with dementia syndromes with or without Parkinsonism 7. Currently, more than 40 pathogenic mutations in MAPT have been described with a wide range of morphological features 7 (see also http://www.molgen.ua.ac.be/ADMutations). This variability allowed one of the pioneer groups of researchers to call hereditary frontotemporal dementia associated with MAPT gene mutations, a chameleon for neuropathology and neuroimaging 7.
Supporting this designation, in the present issue of Neuropathology and Applied Neurobiology, Pawel Tacik and co‐workers from the Mayo Clinic, Jacksonville, FL, USA, present a stimulating study on phenotypic variability associated with one of the most frequent mutations in MAPT, P301L 8. This is not an unprecedented phenomenon in relation to hereditary neurodegenerative diseases, including MAPT mutations 7. What makes it interesting is that most studies on cases with a P301L mutation have focused on neuronal (grey matter) tau pathology, which is predominating also in seven out of eight individuals examined in the study by Tacik et al. 8. When previously described in cases with a P301L mutation, disease‐associated oligodendroglial deposits were not specifically described as globular oligodendroglial inclusions or were morphologically similar to coiled bodies 8. In contrast, a single case from the study by Tacik et al., showed globular glial inclusions and prominent involvement of the white matter compatible with the diagnosis of GGT 8.