Publication news: FUS antibody in recent ALS/FTLD breakthrough
admin September 12, 2011
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PDFMonoclonal FUS antibody 60160-1-Ig appears in recent Brain paper describing markers that distinguish FTLD with FUS pathology (FTLD-FUS) from ALS with FUS mutations (ALS-FUS).
Amyotrophic lateral sclerosis (ALS), sometimes known as Lou Gehrig’s or motor neurone disease (MND), and frontotemporal lobar degeneration (FTLD) are diseases that have outward etiologies similar in nature. TAR-DNA binding protein 43kDa (TDP-43) has been identified as the main disease protein in both ALS and the most common forms of FTLD [1-2]. This finding led to the current theory that the roots of ALS and FTLD are most likely to lie in discrepancies in RNA metabolism. This suggested disease mechanism further crystallized upon the subsequent discovery that the DNA/RNA binding protein fused in sarcoma (FUS) can accumulate as cytoplasmic inclusions in both ALS-FUS and some sub-types of FTLD [3-11]. However, the cause of accumulation of FUS in both diseases is clearly much different: in ALS-FUS the FUS gene harbors mutations which actively lead to cytosolic accumulation of its protein [12-13]. Conversely, no genetic alterations of FUS have been reported in FTLD-FUS to date [11 and 14]. The search for the underlying mechanism in FUS accumulation in FTLD-FUS is on.
IF image of an aFTLD-U case. (FUS inclusions – monoclonal FUS 60160-1-Ig (red); nuclei – DAPI (blue).) Provided by Prof. M. Neumann
Manuela Neumann of the institute of Neuropathology at the University Hospital Zurich, Switzerland is an ALS and FTLD expert looking for answers to the many questions surrounding these diseases. She had a key role in the TDP-43 discovery and helped link FUS to both diseases. Now Neumann and colleagues are looking for other proteins that play a role in the pathologies of ALS and FTLD, and are examining the differences between their disease mechanisms in each case. Their latest paper, published this August in Brain [15], describes their latest and most intriguing finding that two other proteins, related to FUS, can distinguish one disease from the other. Not only this, the finding sheds more light on the elusive mechanism behind FUS accumulation in FTLD-FUS.
Neumann and colleagues had a hunch that FUS-related proteins may also end up in the tangle of FUS inclusions in the cytoplasm of either ALS-FUS and FTLD-FUS affected neurons and glial cells. Following this up, what they found was rather interesting indeed.
FUS is a member of a family of proteins known as FET proteins that have been shown to interact with one another and are thought to form protein complexes [16-17]. The FET family also includes Ewing’s sarcoma (EWS) and TATA-binding protein associated factor 15 (TAF15). After performing detailed immunohistochemical, biochemical and genetic analyses of both TAF15 and EWS in a range of cases covering the full spectrum of FTLD and ALS FUS-opathies, the group had some striking data in their hands. ALS-FUS immunohistochemistry revealed that this pathology stained exclusively for FUS, whereas FTLD-FUS consistently stained for TAF15 and variably for EWS. Immunoblot using FTLD-FUS post-mortem tissue revealed a shift of all FET proteins towards insoluble protein fractions. This confirms that protein inclusions in the two FUS-opathies, ALS-FUS and FTLD-FUS, arise via very different pathological mechanisms: ALS-FUS seems to be restricted to dysfunction of FUS whereas a universal and complex dysregulation of all FET proteins contributes to the subtypes of FTLD-FUS [15].
Data provided by Prof. Manuela Neumann
Interestingly, genetic evaluation of both EWS and TAF15 did not identify any pathogenic variants in these genes; which leaves the question of the genetic mechanism behind the dysregulation of FET proteins leading to FTLD-FUS wide open.
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[11] Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 2009; 132: 2922–31.
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[14] Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie IR. Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 2009; 118:605–16.
[15] Neumann et al., FET proteins TAF15 and EWS are selective markers for FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain 2011 [ahead of print].
[16] Pahlich S, Zakaryan RP, Gehring H. Identification of proteins interacting with protein arginine methyltransferase 8: the Ewing sarcoma (EWS) protein binds independent of its methylation state. Proteins 2008; 72: 1125–37.
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