Tetter S, Arseni D, Murzin AG, Buhidma Y, Peak-Chew SY, Garringer HJ, Newell KL, Vidal R, Apostolova LG, Lashley T, Ghetti B, Ryskeldi-Falcon B. TAF15 amyloid filaments in frontotemporal lobar degeneration. Nature. 2024 Jan;625(7994):345-351. Epub 2023 Dec 6 PubMed.
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Stanford University
A unifying theme for neurodegenerative disorders is the abnormal accumulation of protein aggregates in the central nervous systems of affected individuals. Over the last ~20 years, the isolation of the proteinaceous building blocks of these pathological deposits has provided tremendous insight into disease mechanisms. Genetics discoveries have often gone hand in glove with the biochemical discoveries and, indeed, mutations in several of the genes encoding the aggregation-prone proteins are causative for rare familial forms of the disease. For example, APP (encodes Aβ) mutations or gene triplication cause early onset Alzheimer disease, SNCA (encodes α-synuclein) mutations cause early onset Parkinson disease, MAPT (encodes tau protein) mutations cause frontotemporal dementia, and TARDBP (encodes TDP-43 protein) mutations cause ALS. Filamentous forms of a C-terminal fragment of the TMEM106B protein have recently been discovered in the brains of older individuals and those with neurodegenerative disease. TMEM106B has been linked genetically to FTLD-TDP-43 through genome-wide association studies (GWAS, Van Deerlin et al., 2010). All of this is to say that identifying a new aggregated protein in a neurodegenerative disease is of great interest and will likely be highly informative and impactful.
For frontotemporal lobar degeneration (FTLD), cases can be divided into three major types, based on pathology (Cairns et al., 2007; Mackenzie and Neumann, 2016): 1) FTLD-Tau, which is characterized by tau inclusions; 2) FTLD-TDP-43, which is characterized by TDP-43 inclusions; and a rarer subtype, FTLD-FUS, which is characterized by FUS inclusions.
This paper by Ryskeldi-Falcon and colleagues presents TAF15 as the disease protein in FTLD-FUS cases (contrary to it being FUS, as expected). The authors isolate amyloid material from the brains of 4 FTLD-FUS patients and apply cryo-EM approaches to obtain models of the filamentous material, revealing it to be TAF15.
It had already been known that TAF15 pathology is a component of FTLD-FUS cases, and this subtype is indeed now known as FTLD-FET (for FUS, EWSR1, TAF15) (Neumann et al., 2011; Neumann and Mackenzie, 2019). FUS, EWSR1, and TAF15 are three very similar RNA-binding proteins. However, the new Cryo-EM studies and other analyses now show that it is only TAF15 but not EWSR1 or FUS (or any other amyloid) in the pathological deposits. This is very exciting and novel and of great interest. It really changes how the field will think about this disease and will launch efforts to study TAF15 and perhaps target it for therapy.
In a broader sense, this finding might help explain the different observations between FTLD-FUS (not caused by FUS mutations and FUS, EWSR1, TAF15, and transportin1 are present in pathological inclusions) and ALS-FUS (caused by FUS mutations and only FUS is present in pathological inclusions).
Many questions lie ahead. The authors hypothesize that TAF15 amyloids might sequester into pathological inclusions the proteins FUS, EWSR1, and transportin, a transport protein that recognizes these three RNA-binding proteins and shuttles them into the nucleus. To test this hypothesis, experiments in cell culture and in vitro, i.e., introducing TAF15 amyloids into cells and testing if this causes mislocalization of the other endogenous proteins, will be informative. The FET proteins are highly similar at the primary sequence level, so what makes TAF15 the one that forms amyloids more readily than the others? Would lowering levels of TAF15 or otherwise preventing its aggregation afford clinical benefit? Answering these questions will provide insight and motivate launching of drug discovery programs targeting TAF15 with ASOs or small molecule degraders as a therapy for this rare form of FTLD.
References:
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Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, White CL, Schneider JA, Grinberg LT, Halliday G, Duyckaerts C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Murayama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DM, . Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol. 2007 Jul;114(1):5-22. PubMed.
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Neumann M, Bentmann E, Dormann D, Jawaid A, Dejesus-Hernandez M, Ansorge O, Roeber S, Kretzschmar HA, Munoz DG, Kusaka H, Yokota O, Ang LC, Bilbao J, Rademakers R, Haass C, Mackenzie IR. FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain. 2011 Sep;134(Pt 9):2595-609. PubMed.
Neumann M, Mackenzie IR. Review: Neuropathology of non-tau frontotemporal lobar degeneration. Neuropathol Appl Neurobiol. 2019 Feb;45(1):19-40. PubMed.
View all comments by Aaron GitlerUniversity of British Columbia
The finding for filaments composed of TAF-15 is interesting but not entirely unexpected. We initially introduced the terminology “FTLD-FUS” for these subtypes of tau/TDP-negative FTLD because FUS was the first protein component of the inclusions identified (Neumann et al., 2009); a discovery prompted by the identification of FUS mutations in ALS. However, once we determined that the inclusions also label for the other FET proteins (TAF15, EWS), we suggested that FTLD-FET might be a more appropriate designation (Neumann et al., 2011).
Even at that time, there were some hints that TAF15 might play a more central role in these conditions: (i) of the three FET proteins, TAF15 showed the greatest shift to the insoluble protein fraction, (ii) inclusions are more strongly and consistently labelled with antibodies against TAF15, and (iii) only TAF15 consistently showed loss of the normal physiological nuclear immunoreactivity in inclusion bearing cells, suggesting a possible loss of function.
As the authors indicate, an important issue is whether or not there are differences among the FTLD-FET subtypes (aFTLD-U, -NIFID, -BIBD) in the pathological filaments.
With that in mind, I would point out that although the authors of this paper have designated all four cases used in their study as being examples of aFTLD-U, the morphology and anatomical distribution of the inclusions and the associated clinical phenotypes of some of the cases (e.g. ALS) would be more consistent with either NIFID or BIBD.
Additional cryo-EM analysis of additional, well-characterized cases is needed.
One minor aspect of the study that is unclear to me is why biochemical analysis of the insoluble protein fraction does not disclose any disease-specific low-molecular-weight TAF15 band corresponding to the filament core.
References:
Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain. 2009 Nov;132(Pt 11):2922-31. PubMed.
Neumann M, Bentmann E, Dormann D, Jawaid A, Dejesus-Hernandez M, Ansorge O, Roeber S, Kretzschmar HA, Munoz DG, Kusaka H, Yokota O, Ang LC, Bilbao J, Rademakers R, Haass C, Mackenzie IR. FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain. 2011 Sep;134(Pt 9):2595-609. PubMed.
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