TMEM106B Aggregates in Neurodegenerative Disease

Researchers here report on their identification of a novel form of protein aggregate in the aging human brain, involving altered TMEM106B, associated with multiple types of neurodegenerative condition. It is far too early to talk about how greatly this dysfunction contributes to specific conditions, versus other, better characterized mechanisms. Determining whether it is important or a curiosity will be the work of years yet. The pace at which novel mechanisms such as this are discovered might give us some insight into how much more there is to be discovered in the biochemistry of the aging brain. TDP-43, another protein capable of aggregating, is also discussed in this paper, and it is worth noting that the relevance of TDP-43 to neurodegeneration is also a comparatively recent discovery.

Neurodegenerative proteinopathies are characterized by the deposition of filamentous protein aggregates in neurons and/or glia. The transactive response DNA-binding protein-43 (TDP-43), the microtubule-associated phosphoprotein tau, and α-synuclein protein can each misfold and accrue intracellularly into tangled filamentous inclusions manifesting in neurodegenerative diseases known collectively as TDP-43 proteinopathies, tauopathies, and synucleinopathies, respectively. The structures of TDP-43 and tau filaments in frontotemporal lobar degeneration (FTLD) and α-synuclein fibrils in multiple system atrophy (MSA) have recently been reported. What has emerged from these studies is that each disease has a homotypic molecular fold, or conformer, characteristic of the underlying neuropathology. The evidence for the "one conformer per disease" paradigm is growing, with the presence of unknown buried cofactors mediating the structural diversity of fibrillar polymorphs.

Here, using a combination of cryoelectron microscopy (cryo-EM) and mass spectrometry (MS), we show that a previously unsolved amyloid fibril found in cases representing a variety of neurodegenerative conditions is composed of a 135 amino acid C-terminal fragment of TMEM106B, a known risk gene for FTLD-TDP and aging. The fibrillization of TMEM106B into identical fibrillar structures in a wide range of sporadic or genetic TDP-43 proteinopathies (FTLD-TDP), a tauopathy (progressive supranuclear palsy), and a synucleinopathy (dementia with Lewy bodies) points toward a commonality between these diverse neurodegenerative diseases. This suggests that the formation of amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, may contribute to pathogenicity via a loss or gain of function.


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