Article ; Online: Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS in UBQLN2 p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia.
Brain pathology (Zurich, Switzerland)
2023 Volume 34, Issue 3, Page(s) e13230
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 ...
| 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. |
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| MeSH term(s) | Humans ; Adaptor Proteins, Signal Transducing/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Autophagy-Related Proteins/metabolism ; DNA-Binding Proteins/metabolism ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Mutation ; Transcription Factors/metabolism | |||||
| Chemical Substances | Adaptor Proteins, Signal Transducing ; Autophagy-Related Proteins ; DNA-Binding Proteins ; Transcription Factors ; UBQLN2 protein, human ; TARDBP protein, human | |||||
| Language | English | |||||
| Publishing date | 2023-12-19 | |||||
| Publishing country | Switzerland | |||||
| Document type | Journal Article | |||||
| ZDB-ID | 1051484-3 | |||||
| ISSN | 1750-3639 ; 1015-6305 | |||||
| ISSN (online) | 1750-3639 | |||||
| ISSN | 1015-6305 | |||||
| DOI | 10.1111/bpa.13230 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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