Accumulation of TMEM106B C-terminal fragments in Niemann-Pick type C disease

To the Editor: The lysosomal diseases are a class of over 60 genetic disorders with a shared pathology of accumulated lysosomal substrates and organellar dysfunction.1 Like most lysosomal diseases, Niemann-Pick type C disease (NPC) is rare, with an incidence of ∼1/100 000 live births.2 NPC is caused by loss-of-function mutations in the NPC1 (95% of cases) or NPC2 (5% of cases) genes, both of which encode proteins required for cholesterol export from late endosomes and lysosomes.2 As a result, NPC patients have disease-characterizing accumulations of cholesterol and gangliosides in these organelles in numerous cell types. Clinical manifestations include progressive neurodegeneration and early death.2 CNS pathology is characterized by brain atrophy, swollen neuronal cell bodies, and neuroaxonal dystrophy.3,4 These features are often accompanied by an accumulation of misfolded proteins including tau,4 alpha-synuclein,3 and amyloid-beta,5 suggesting an impairment of protein quality control. Recent studies have identified TMEM106B C-terminal aggregates in several age-related neurodegenerative proteinopathies, including frontotemporal lobar degeneration (FTLD),6–8 tauopathies,6,8 and synucleinopathies,6,8 as well as in normal, aged brains.6,9 This pathology has been demonstrated in individuals ranging in age from 41 to 101 years.6,9 These C-terminal fragments are derived from TMEM106B, a late endosome and lysosome transmembrane protein that is highly expressed in neurons and glia.6 The protein undergoes intramembranous cleavage to generate N- and C-terminal fragments, the latter of which form amyloid filaments.10 Furthermore, a TMEM106B genetic variant has been identified as a risk factor for FTLD-TDP.11,12 Here, we present a case of NPC with an accumulation of TMEM106B C-terminal fragments. This is the first description of TMEM106B C-terminal fragments in a lysosomal disorder and is the youngest reported individual with this pathology. The patient had a normal birth and reached normal developmental milestones. He graduated from high school and college, and then finished a post-baccalaureate program to become a paralegal. He developed an inability to troubleshoot problems and although he lived independently until age 27, he moved back home after that. He was diagnosed with hearing loss requiring hearing aids at age 26 and then depression and autism spectrum disorder at age 29. While seeing a psychiatrist, he was noted to have a tremor and slow processing speed. He was then referred to Neurology where he was found to have ataxia with inability to do tandem gait, mild dysarthria, mild dysmetria, action tremor, and a vertical supranuclear gaze palsy with slow saccades to both up- and down gaze. By that point, the family noted lack of attention to his environment, writing difficulty, slowness of speech, and difficulty thinking logically. Magnetic resonance imaging showed mild atrophy of the cerebellar vermis. Genetic testing revealed 2 known disease-associated mutations (in trans, based on parental testing) in the NPC1 gene, c.2196dupT, p. Pro733SerfsX10 and c.1301 C > T, p. Pro434Leu. Filipin staining of fibroblasts was consistent with NPC. Miglustat treatment resulted in worsening of tremor and a neuropathy necessitating discontinuance. He was started on intrathecal 2-hydroxypropyl-β-cyclodextrin (adrabetadex) at age 31 with initial stabilization in cognitive scores and other symptoms for about 2 years, but had subsequent progressive dysphagia, decline in cognition and memory, worsening dysmetria, and progressive dystonia resulting in loss of independent ambulation. At age 37, he was switched from adrabetadex to arimoclomol, but ongoing deterioration occurred in all areas with severe memory deficits and dementia. At age 38, he succumbed to a community-acquired pneumonia caused by Haemophilus influenzae with ARDS and acute hypoxic respiratory failure. Postmortem examination revealed an 1100 g brain with moderate depigmentation of the substantia nigra and atrophy of the cerebellar vermis. Cortical sections revealed scattered neurons with ballooned soma filled with storage material (Figure 1A). Immunohistochemical stain for tau highlighted modest pretangles, neuropil threads, and occasional neurofibrillary tangles in neocortex, basal forebrain, and limbic regions (Braak stage IV) (Figure 1B). Lewy pathology was observed in the substantia nigra by an α-synuclein immunostain (Figure 1C). No accumulation of phospho-TDP-43 was present. Notably, an antibody specific to the filament-forming C-terminus of TMEM106B (SB0051)6 showed positive, punctate granular staining in the mid-frontal lobe (Figure 1D-F). C-terminal TMEM106B was detected in scattered neurofilament-positive pyramidal-shaped neurons (Figure 1D and F) and in linear processes (Figure 1E), indicating the presence of TMEM106B pathology in both neuronal cell bodies and axons. No TMEM106B staining was observed in the thalamus or cerebellum, other brain regions affected in NPC, or in the mid-frontal lobe of 3 age-matched controls (not shown). Sequencing of TMEM106B demonstrated that this individual was heterozygous for the coding variant p. T185S (rs3173615), with T185 considered a risk allele for FTLD-TDP.11,12 TMEM106B C-terminal fragments in NPC brain. A-B and D-F: Mid-frontal lobe; C: substantia nigra. Scale bars: A-D = 50 µm; E and F = 10 µm. The accumulation of TMEM106B C-terminal fragments in cortical neurons of a young adult with NPC extends the spectrum of known diseases that display this recently defined pathology. The anatomical and cellular distribution of TMEM106B pathology in this case is more restricted than what has been described previously.6,9 Notably, abundant TMEM106B pathology occurs in individuals with FTLD-TDP with GRN mutations, including those in their 40s and 50s.6,9 Our observations are in keeping with these findings and support the notion that lysosomal stress or dysfunction contributes to the accumulation of C-terminal fragments.6 While the possibility of early, age-related changes cannot be fully excluded in this case, the findings reported here raise the possibility that TMEM106B pathology is even more widespread and occurs in additional lysosomal disorders, perhaps as a consequence of impaired lysosomal degradation. These observations additionally highlight similarities between lysosomal diseases and age-related neurodegenerative proteinopathies in which impairments of lysosome function are increasingly implicated in disease pathogenesis. The authors thank the patient and family for their generous gift of postmortem tissue in support of improving the understanding of the pathogenesis of NPC. This work was supported by grants from the National Institutes of Health (R01 NS122746, P30 AG072931) and Niemann-Pick Canada. The authors have no conflicts of interest to disclose.

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