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:10.1101/2023.02.14.528561

Cited by 3 publications

(3 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lastly, increased microglial proteins were associated with the brown module and showed an increased abundance of lysosomal proteins. This is consistent with findings from transcriptomics of microglia isolated from rNLS8 mouse cortex in early disease 20 , and findings that phagocytic microglia progressively become dysfunctional in the motor cortex in rNLS8 mice and human ALS cases 48 .…”

Section: Discussionsupporting

confidence: 89%

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

Gil,

Pascovici,

Venturato

et al. 2023

Preprint

View full text Add to dashboard Cite

Understanding the mechanisms that drive TDP-43 pathology is integral to combating neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To address this, we sought to determine the timeline of proteomic alterations across disease course in TDP-43 proteinopathy. Using longitudinal quantitative proteomics analysis of cortex samples from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD, we identified several distinct protein subsets characterized by temporal alterations in protein abundance across diverse biological pathways, including protein folding, intracellular transport, myelination, and neuronal synaptic function. Remarkably, neurons in the rNLS8 cortex elicited a transitory response primarily comprising protein-folding factors prior to and in the earliest stages of disease progression. This response included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, and proof-of-concept studies showed that DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures. Conversely, knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in the brains and spinal cords of mice. Lastly, the late disease proteomic signatures of rNLS8 mouse cortex strongly correlated with changes in human autopsy-derived TDP-43 proteinopathy tissues, indicating commonality of disease processes. Together, these findings reveal molecular mechanisms that regulate protein levels through distinct stages of ALS and FTLD progression, and suggest that protein folding factors that combat cytoplasmic TDP-43 protein aggregation could be protective in disease.

show abstract

Section: Discussionsupporting

confidence: 89%

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

Gil,

Pascovici,

Venturato

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Fluorescence immunohistochemistry was performed as described previously [31–33] 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 [18, 29] and the manufacturer confirms is the same clone as that used by [4] and [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 inUBQLN2p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia

Nementzik

Thumbadoo

Murray

et al. 2023

Preprint

View full text Add to dashboard Cite

Mutations in theUBQLN2gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of suchUBQLN2-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 withoutUBQLN2mutations 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 threeUBQLN2p.T487I-linked ALS/FTD cases, three non-UBQLN2-linked (sporadic) ALS cases, and eight 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 howUBQLN2-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 inUBQLN2-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 toUBQLN2-linked ALS/FTD. While ubiquilin 2 deposition in frontotemporal regions may enhance cognitive risk inUBQLN2-linked cases, ubiquilin 2 is deposited mainly in clinically unaffected regions throughout the CNS such that overall symptomology in these cases maps best to the aggregation of TDP-43.

show abstract

“…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 antiubiquilin 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: Multiplexed Fluorescent Immunohistochemistrymentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 3 publications

References 70 publications

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

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

Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS inUBQLN2p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia

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

Contact Info

Product

Resources

About