Microglial CD68 and L-ferritin upregulation in response to phosphorylated-TDP-43 pathology in the amyotrophic lateral sclerosis brain

Swanson, Molly E. V.; Mrkela, Miran; Murray, Helen C.; Cao, Maize C; Turner, Clinton; Curtis, Maurice A.; Faull, Richard L. M.; Walker, Adam K.; Scotter, Emma L.

doi:10.1186/s40478-023-01561-6

Cited by 19 publications

(7 citation statements)

References 70 publications

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“…1a ). The rNLS8 mice at pre-onset (1 wk) show dox-induced neuron-specific expression of the human cytoplasmic TDP-43 transgene and loss of endogenous mouse TDP-43, at onset (2 wk) motor deficits emerge, at early disease (4 wk) there is a decrease in muscle innervation, cortical neuron degeneration and astrogliosis, at late disease (6 wk) there is microglial dysfunction 21 , spinal cord motor neuron degeneration and a dramatic motor deficit 18 . Mice in recovery (6 wk off dox and 2 wk on dox; +rec) show clearance of cytoplasmic TDP-43, restoration of endogenous TDP-43 in neurons, muscle re-innervation from remaining neurons, and regain motor skills 18 .…”

Section: Resultsmentioning

confidence: 99%

A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration

San Gil,

Pascovici,

Venturato

et al. 2024

Nat Commun

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Understanding the mechanisms that drive TDP-43 pathology is integral to combating amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases. Here we generated a longitudinal quantitative proteomic map of the cortex from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD, and developed a complementary open-access webtool, TDP-map (https://shiny.rcc.uq.edu.au/TDP-map/). We identified distinct protein subsets enriched for diverse biological pathways with temporal alterations in protein abundance, including increases in protein folding factors prior to disease onset. This included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, which also co-localized with TDP-43 pathology in diseased human motor cortex. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. Together, these findings reveal molecular mechanisms at distinct stages of ALS and FTLD progression and suggest that protein folding factors could be protective in neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration

San Gil,

Pascovici,

Venturato

et al. 2024

Nat Commun

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“… 72-75 This could explain the upregulation in CD68 expressing cells we measured in the pons in the non-GA ataxia control group as a potential response to axonal degeneration and synaptic loss. 76 , 77 …”

Section: Discussionmentioning

confidence: 99%

Cerebellar degeneration in gluten ataxia is linked to microglial activation

Floare,

Wharton,

Simpson

et al. 2024

Brain Communications

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Gluten sensitivity has long been recognised exclusively for its gastrointestinal involvement, however more recent research provides evidence for the existence of neurological manifestations that can appear in combination with, or independent of the small bowel manifestations. Amongst all neurological manifestations of gluten sensitivity, Gluten ataxia is the most commonly occurring one, accounting for up to 40% of cases of idiopathic sporadic ataxia. However, despite its prevalence, its neuropathological basis is still poorly defined. Here we provide a neuropathological characterisation of gluten ataxia and compare the presence of neuroinflammatory markers GFAP, Iba-1, MHC-II and CD68 in the central nervous system of 4 gluten ataxia cases to 5 ataxia controls and 7 neurologically healthy controls. Our results demonstrate that severe cerebellar atrophy, CD20+ and CD8+ lymphocytic infiltration in the cerebellar grey and white matter and a significant upregulation of microglial immune activation in the cerebellar granular layer, molecular layer, and cerebellar white matter are features of Gluten ataxia, providing evidence for the involvement of both cellular and humoral immune-mediated processes in gluten ataxia pathogenesis.

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“…Fluorescence immunohistochemistry was performed as described previously [ 30 , 31 , 32 ] using primary and secondary antibodies as described in Tables S4 and S5 . The ubiquilin 2 antibody used here (mouse monoclonal anti‐ubiquilin IgG 2a , Santa Cruz #SC‐100612) has been used by us previously for the detection of neuropathological aggregates [ 11 , 18 ] and which the manufacturer confirms is the same clone as that used by [ 4 , 12 ] (mouse monoclonal anti‐ubiquilin IgG 2a , clone 5F5, Novus Biologicals #H00029978‐M03).…”

Section: Methodsmentioning

confidence: 99%

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

Nementzik,

Thumbadoo,

Murray

et al. 2023

Brain Pathology

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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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Microglial CD68 and L-ferritin upregulation in response to phosphorylated-TDP-43 pathology in the amyotrophic lateral sclerosis brain

Cited by 19 publications

References 70 publications

A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration

A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration

Cerebellar degeneration in gluten ataxia is linked to microglial activation

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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