Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology

Abstract

The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia-ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann-Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new heterozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.

Keywords: cerebellar ataxia; movement disorders; neurogenetics; postmortem.

Figure 1

Brain magnetic resonance imaging (MRI) and single-photon emission computed tomography (DaTscan) obtained four years after symptom onset. (A) Brain MRI Left panel: mid-sagittal T1-weighted sequence with mild vermal cerebellar atrophy and midbrain atrophy (midbrain anteroposterior diameter, 8.6 mm; midbrain-to-pons ratio 0.54) [6]; central panel: axial T2 FLAIR sequence showing mild tegmental midbrain atrophy; right panel: axial T2 FLAIR sequence showing two small white matter hyperintensities. (B) DaTscan showed asymmetric (right > left), abnormally decreased uptake in the bilateral putamen and right caudate.

Figure 2

Brain neuropathology, microscopic anatomy: (A) immunohistochemistry staining showing tau accumulation in the putamen, predominantly in the form of tufted astrocytes and tau-positive neurons (100× magnification); (B) immunohistochemistry staining showing tufted astrocytes in the caudate nucleus (200× magnification); (C,D) substantia nigra showing neuronal cell loss, tau-positive neurons, and numerous neuropil threads ((C) hematoxylin and eosin staining; (D) immunohistochemistry staining; 100× magnification).

Figure 3

Immunostaining for 4R (left and middle column) and 3R (right column) tau isoforms in the subthalamic nucleus, putamen, globus pallidus, substantia nigra, and locus coeruleus. Note that the pathology is predominated by 4R tau deposition and shows tufted astrocytes (few examples indicated by arrows), globose neurofibrillary tangles (few examples indicated by arrowheads), and coiled bodies (few examples indicated by asterisks). Only a single 3R tau immunoreactive neurofibrillary tangle is seen in the locus coeruleus (arrowhead), and two are seen weakly stained in the subthalamic nucleus (arrowheads).

Figure 4

In vitro assay showing TG6 transamidase activity: (A) Western blotting analysis showed significantly compromised transamidase activity of the TGM6 T206P variant compared to wild-type TG6 protein. (B) Quantification of TG6 enzymatic activity from experiment shown in panel A. Graph, mean ± SEM, * p <0.05, one-way ANOVA with Tukey’s post hoc test. Y-Axis represents the fold change.