Identification of TMEM106B amyloid fibrils provides an updated view of TMEM106B biology in health and disease

Abstract

Since the initial identification of TMEM106B as a risk factor for frontotemporal lobar degeneration (FTLD), multiple genetic studies have found TMEM106B variants to modulate disease risk in a variety of brain disorders and healthy aging. Neurodegenerative disorders are typically characterized by inclusions of misfolded proteins and since lysosomes are an important site for cellular debris clearance, lysosomal dysfunction has been closely linked to neurodegeneration. Consequently, many causal mutations or genetic risk variants implicated in neurodegenerative diseases encode proteins involved in endosomal–lysosomal function. As an integral lysosomal transmembrane protein, TMEM106B regulates several aspects of lysosomal function and multiple studies have shown that proper TMEM106B protein levels are crucial for maintaining lysosomal health. Yet, the precise function of TMEM106B at the lysosomal membrane is undetermined and it remains unclear how TMEM106B modulates disease risk. Unexpectedly, several independent groups recently showed that the C-terminal domain (AA120-254) of TMEM106B forms amyloid fibrils in the brain of patients with a diverse set of neurodegenerative conditions. The recognition that TMEM106B can form amyloid fibrils and is present across neurodegenerative diseases sheds new light on TMEM106B as a central player in neurodegeneration and brain health, but also raises important new questions. In this review, we summarize current knowledge and place a decade’s worth of TMEM106B research into an exciting new perspective.

Cross-β helical filaments of Tau and TMEM106B in Gray and White Matter of Multiple System Tauopathy with presenile Dementia

“…The change (rs 147889591) was confirmed by direct sequencing. We also analyzed a number of TMEM106B interacting partners [8]. A total of 20 genes were analyzed.…”

“…TMEM106B is a lysosomal transmembrane protein vital for lysosomal health and has been implicated as a risk factor and/or disease modulator in many neurodegenerative diseases [8]. Recently, while investigating ex-vivo filaments from individuals affected by neurodegenerative diseases, it was serendipitously discovered that TMEM106B filaments co-exist with other aggregated protein filaments in sporadic and inherited tauopathies, amyloid-β amyloidoses, synucleinopathies and TDP-43 proteinopathies [10][11][12][13].…”

“…In addition to the TMEM106B gene, the coding regions of genes corresponding to proteins reported to interact with the TMEM106B protein were screened for variants. These genes include APOE, CHMP2B, CTSD, GRN, KCNMA1, KCNMB2, LAMTOR1, MAP6, MYLK, NSF, PLD3, RFC5, STX7, TARDP, TMEM106A, TMEM106B, TMEM106C, TMEM192, VAMP7 , and VPS11 [8].…”

“…The transmembrane protein 106B (TMEM106B) is known to be associated with risk in neurodegenerative diseases and specifically frontotemporal dementias; however, the relationship between TMEM106B and tau is not well understood [7,8]. At the cellular level, there is evidence that this protein is present in neurons, oligodendrocytes, astrocytes and microglia [8,9]. By cryo-EM, TMEM106B filaments were recently identified in postmortem brain tissue of individuals affected by neurodegenerative diseases and of individuals with no evidence of neurodegeneration [10][11][12][13].…”

“…The transmembrane protein 106B (TMEM106B) is known to be associated with risk in neurodegenerative diseases and specifically frontotemporal dementias; however, the relationship between TMEM106B and tau is not well understood [7, 8]. At the cellular level, there is evidence that this protein is present in neurons, oligodendrocytes, astrocytes and microglia [8, 9].…”