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. 2024 May;34(3):e13230.
doi: 10.1111/bpa.13230. Epub 2023 Dec 19.

Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS in UBQLN2 p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia

Laura R Nementzik  1   2 , Kyrah M Thumbadoo  1   2 , Helen C Murray  2   3 , David Gordon  1   2 , Shu Yang  4 , Ian P Blair  4 , Clinton Turner  2   3   5 , Richard L M Faull  2   3 , Maurice A Curtis  2   3 , Catriona McLean  6 , Garth A Nicholson  4   7   8 , Molly E V Swanson  1   2 , Emma L Scotter  1   2
Affiliations

Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS in UBQLN2 p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia

Laura R Nementzik et al. Brain Pathol. 2024 May.

Abstract

Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2-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 UBQLN2 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 UBQLN2 p.T487I-linked ALS/FTD cases, three non-UBQLN2-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 UBQLN2-linked and non-UBQLN2-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 UBQLN2-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 UBQLN2-linked ALS/FTD. Overall, ubiquilin 2 is mainly deposited in clinically unaffected regions throughout the CNS such that symptomology in UBQLN2-linked cases maps best to the aggregation of TDP-43.

Keywords: TDP‐43; UBQLN2; amyotrophic lateral sclerosis (ALS); frontotemporal dementia (FTD); neuropathology; ubiquilin 2.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

FIGURE 1
FIGURE 1
Ubiquilin 2 and TDP‐43 labelling in previous studies largely fails to discriminate between independent aggregation and co‐aggregation. Schematic summary of literature describing ubiquilin 2 and TDP‐43 neuropathology in UBQLN2‐linked human ALS/FTD. Ubiquilin 2 aggregates (green box with plus) or TDP‐43 aggregates (red box with plus) in each CNS region were either; not both tested (one plus or minus), not both identified (one plus, one minus), both identified but co‐localisation not tested (dashed black box) or co‐localised (shared black box). *Co‐localisation in certain cases only. Amg, amygdala; CA, cornu ammonis; GCL, granule cell layer; HN, hypoglossal nucleus; ION, inferior olivary nucleus; MC, motor cortex; ML, molecular layer; NCx, neocortex; PHG, parahippocampal gyrus; PL, polymorphic layer; Put, putamen; SC, spinal cord; Thal, thalamus.
FIGURE 2
FIGURE 2
Morphology of ubiquilin 2 aggregates in UBQLN2 p.T487I‐linked ALS/FTD. Sections from across the CNS from representative UBQLN2 p.T487I‐linked ALS/FTD case V:7 (A, C, E) and representative stage 4 sALS case MN30 (B, D, F). Spinal cord ventral horn (VH) motor neurons demonstrated large TDP‐43 aggregates (red) that were negative for ubiquilin 2 (green) in both UBQLN2 p.T487I‐linked ALS/FTD (A) and stage 4 sALS (B). Dorsal horn (DH) demonstrated small punctate ubiquilin 2 aggregates (green) that were negative for TDP‐43 (red) in UBQLN2 p.T487I‐linked ALS/FTD (C) and in stage 4 sALS where they were smaller and dot‐like (D). Motor cortex demonstrated small punctate ubiquilin 2 aggregates (green) that were negative for TDP‐43 (red) in UBQLN2 p.T487I‐linked ALS/FTD (E′) and in stage 4 sALS where they were dot‐like (F′); and TDP‐43 aggregates (red) that were negative for ubiquilin 2 (green) in both UBQLN2 p.T487I‐linked ALS/FTD (E″) and stage 4 sALS (F″). Scale bars 20 μm.
FIGURE 3
FIGURE 3
Ubiquilin 2‐only and TDP‐43‐only aggregates in the UBQLN2 p.T487I‐linked ALS/FTD hippocampal formation and entorhinal and perirhinal cortices. Hippocampal sections from 2 UBQLN2 p.T487I‐linked ALS/FTD cases (A–J″) demonstrated punctate aggregates in the dentate gyrus molecular layer (A 1 , B 1 ) that were positive for ubiquilin 2 only (A 1 ′, B 1 ′, green) and negative for TDP‐43 (A 1 ″, B 1 ″). Case V:7 showed rare granule cell layer cytoplasmic aggregates of TDP‐43 only (B 2 ″, red) that were negative for ubiquilin 2 (B 2 ′). Cornu ammonis and parahippocampal subregions showed abundant punctate ubiquilin 2‐only aggregates (C′–J′) and fewer TDP‐43‐only aggregates (C″–J″) that were each negative for the other protein. Quantification of the density of ubiquilin 2‐only (green) and TDP‐43‐only (red) aggregates showed that in UBQLN2 p.T487I‐linked ALS/FTD cases both aggregate types were highest in subiculum (K), while in stage 4 sALS ubiquilin 2‐only aggregates were rare or absent but TDP‐43‐only aggregates were found throughout the hippocampal formation, particularly in the granule cell layer (L). Scale bars in A, B, 100 μm; others 20 μm. CA, cornu ammonis; EC, entorhinal cortex; GCL, granule cell layer; ML, molecular layer; PC, piriform cortex; PL, polymorphic layer; Sub, subiculum.
FIGURE 4
FIGURE 4
Ubiquilin 2‐only and TDP‐43‐only aggregates in the UBQLN2 p.T487I‐linked ALS/FTD spinal cord. Spinal cord sections from 3 UBQLN2 p.T487I‐linked ALS/FTD cases (A–F 1 ″) demonstrated punctate aggregates in the dorsal horn (A–C) that were positive for ubiquilin 2 only (A 1 ′–C 1 ′, green) and negative for TDP‐43 (A 1 ″–C 1 ″). The ventral horns showed abundant cytoplasmic and neuropil TDP‐43‐only aggregates (D 1 ″–F 1 ″, red) that were negative for ubiquilin 2 (D 1 ′–F 1 ′). Quantification of the density of aggregates confirmed that in UBQLN2 p.T487I‐linked ALS/FTD cases ubiquilin 2‐only aggregates (green) were most abundant in the dorsal horn but TDP‐43‐only aggregates (red) were most abundant in the ventral horn (highlighted by pale red shading) (G). The same pattern was observed in stage 4 sALS cases but with only rare ubiquilin 2‐only aggregates in the dorsal horn (H). Scale bar in main images, 200 μm; in insets 20 μm. DGM, dorsal grey matter; DWM, dorsal white matter; VGM, ventral grey matter; VWM, ventral white matter.
FIGURE 5
FIGURE 5
Ubiquilin 2‐only and TDP‐43‐only aggregates in the UBQLN2 p.T487I‐linked ALS/FTD motor cortex. Motor cortex sections from 3 UBQLN2 p.T487I‐linked ALS/FTD cases (A–C 5 ) demonstrated aggregates in the cortical layers I‐VI that were positive for ubiquilin 2 only (green) or TDP‐43 only (red), but rarely positive for both (A 1 –A 5 , B 1 –B 5 , C 1 –C 5 ). Quantification of the density of aggregates demonstrated that in UBQLN2 p.T487I‐linked ALS/FTD cases ubiquilin 2‐only aggregates (green) were most abundant in layer VI, but TDP‐43‐only aggregates (red) were found throughout the cortical layers with case IV:10 showing higher density in layers III and V (highlighted by pale red shading) (D). Stage 4 sALS cases showed very rare ubiquilin 2‐only aggregates but TDP‐43‐only aggregates were found throughout the cortical layers (E). Scale bar in main images, 200 μm; in insets 20 μm. GM, grey matter; WM, white matter.
FIGURE 6
FIGURE 6
Ubiquilin 2‐only and TDP‐43‐only aggregates in the UBQLN2 p.T487I‐linked ALS/FTD striatum. Striatal sections from 2 UBQLN2 p.T487I‐linked ALS/FTD cases demonstrated abundant punctate and some large diffuse aggregates in the putamen, caudate nucleus and ventral striatum, that were positive for ubiquilin 2 only and negative for TDP‐43 (A–E 2 , green). TDP‐43‐only aggregates were also present in these subregions but were less abundant (A–E 2 , red). Quantification of the density of aggregates confirmed that in UBQLN2 p.T487I‐linked ALS/FTD cases ubiquilin 2‐only aggregates (green) were more abundant than TDP‐43‐only aggregates (red) (F). Stage 4 sALS case MN30 showed deposition of ubiquilin 2‐only aggregates in putamen and ventral striatum, while case MN15 showed particularly abundant TDP‐43‐only aggregates across the striatum (G). Confocal imaging of the caudate nucleus (H) showed few large diffuse ubiquilin 2 aggregates (green, H 1 ) and many small punctate ubiquilin 2 aggregates (green, H 2 ). Scale bar in main images A‐E, 100 μm; in insets of A‐E and in image H, 20 μm; in insets of H, 5 μm. CN, caudate nucleus; Put, putamen; VS, ventral striatum.
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