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

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.