Nementzik, Laura R.;
Thumbadoo, Kyrah M.;
Murray, Helen C.;
Gordon, David;
Yang, Shu;
Blair, Ian P.;
Turner, Clinton;
Faull, Richard L. M.;
Curtis, Maurice A.;
McLean, Catriona;
Nicholson, Garth A.;
Swanson, Molly E. V.;
Scotter, Emma L.
Distribution of ubiquilin 2 and TDP‐43 aggregates throughout the CNS in UBQLN2 p.T487I‐linked amyotrophic lateral sclerosis and frontotemporal dementia
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Medientyp:
E-Artikel
Titel:
Distribution of ubiquilin 2 and TDP‐43 aggregates throughout the CNS in UBQLN2 p.T487I‐linked amyotrophic lateral sclerosis and frontotemporal dementia
Beteiligte:
Nementzik, Laura R.;
Thumbadoo, Kyrah M.;
Murray, Helen C.;
Gordon, David;
Yang, Shu;
Blair, Ian P.;
Turner, Clinton;
Faull, Richard L. M.;
Curtis, Maurice A.;
McLean, Catriona;
Nicholson, Garth A.;
Swanson, Molly E. V.;
Scotter, Emma L.
Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Mutations in the <jats:italic>UBQLN2</jats:italic> gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such <jats:italic>UBQLN2</jats:italic>‐linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the transactive response DNA‐binding protein of 43 kDa (TDP‐43). ALS and FTD without <jats:italic>UBQLN2</jats:italic> mutations are also characterised by TDP‐43 aggregates, that may or may not colocalise with wildtype ubiquilin 2. Despite this, the relative contributions of TDP‐43 and ubiquilin 2 to disease pathogenesis remain largely under‐characterised, as does their relative deposition as aggregates across the central nervous system (CNS). Here we conducted multiplex immunohistochemistry of three <jats:italic>UBQLN2</jats:italic> p.T487I‐linked ALS/FTD cases, three non‐<jats:italic>UBQLN2</jats:italic>‐linked (sporadic) ALS cases, and 8 non‐neurodegenerative disease controls, covering 40 CNS regions. We then quantified ubiquilin 2 aggregates, TDP‐43 aggregates and aggregates containing both proteins in regions of interest to determine how <jats:italic>UBQLN2</jats:italic>‐linked and non‐<jats:italic>UBQLN2</jats:italic>‐linked proteinopathy differ. We find that ubiquilin 2 aggregates that are negative for TDP‐43 are predominantly small and punctate and are abundant in the hippocampal formation, spinal cord, all tested regions of neocortex, medulla and substantia nigra in <jats:italic>UBQLN2</jats:italic>‐linked ALS/FTD but not sporadic ALS. Curiously, the striatum harboured small punctate ubiquilin 2 aggregates in all cases examined, while large diffuse striatal ubiquilin 2 aggregates were specific to <jats:italic>UBQLN2</jats:italic>‐linked ALS/FTD. Overall, ubiquilin 2 is mainly deposited in clinically unaffected regions throughout the CNS such that symptomology in <jats:italic>UBQLN2</jats:italic>‐linked cases maps best to the aggregation of TDP‐43.</jats:p>