Striatal transcriptome changes linked to drug‐induced repetitive behaviors

Crittenden, Jill R.; Gipson, Theresa A.; Smith, Anne C.; Bowden, Hilary A.; Yildirim, Ferah; Fischer, Kathleen M.; Yim, Michael; Housman, David E.; Graybiel, Ann M.

doi:10.1111/ejn.15116

Cited by 10 publications

(5 citation statements)

References 106 publications

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“…In related work, DNAJB5 was identified as a component of a synaptic protein complex, along with 11 sodium and calcium voltage-gated ion channels, in BraInMap, a global proteomic investigation of 1000 multi-protein complexes in the brain 81 . Dnajb5 transcripts are also upregulated in the striatum of rodents treated with psychostimulants MDMA 82 , and D-amphetamine 83 , and L-DOPA 84 . Further, Dnajb5 transcripts are significantly increased in hippocampus of an epileptic mouse model with hyperexcitability 85 , a mouse model of moderate glutamate hyperactivity 86 , and pentylenetetrazole-induced excitotoxicty 87 in published microarray and RNAseq datasets.…”

Section: Discussionmentioning

confidence: 98%

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: Discussionmentioning

confidence: 98%

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

View full text Add to dashboard Cite

show abstract

“…In related work, DNAJB5 was identified as a component of a synaptic protein complex, along with 11 sodium and calcium voltage-gated ion channels, in "BraInMap", a global proteomic investigation of 1000 multi-protein complexes in the brain 60 . Dnajb5 transcripts are also upregulated in the striatum of rodents treated with psychostimulants MDMA (ecstasy) 61 , and D-amphetamine 62 , and L-DOPA 63 . Further, Dnajb5 transcripts are significantly increased in mouse hippocampus of an epileptic mouse model with hyperexcitability 64 , a mouse model of moderate glutamate hyperactivity 65 , and pentylenetetrazole-induced excitotoxicty 66 in published microarray and RNAseq datasets.…”

Section: Discussionmentioning

confidence: 99%

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

Gil,

Pascovici,

Venturato

et al. 2023

Preprint

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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.

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“…Understanding the biological basis of phenotypic heterogeneity is essential to discover treatment biomarkers [ 2 ]. RRBs comprise one of the core symptom domains of ASD; however, these behaviors are observed in multiple neuropsychiatric conditions (e.g., schizophrenia, bipolar disorder, obsessive-compulsive disorder, drug addiction, L-DOPA-induced dyskinesia, and Huntington’s disease) [ 61 ]. Moreover, RRBs are observed in diverse genetic syndromes (e.g., Prada-Willie syndrome, Fragile X syndrome, and Rett syndromes) and are likely to be associated with multiple neurotransmitters such as GABA, dopamine, glutamate, and serotonin [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Quantitative trait locus analysis for endophenotypes reveals genetic substrates of core symptom domains and neurocognitive function in autism spectrum disorder

2022

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Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders and is largely attributable to genetic risk factors. Phenotypic and genetic heterogeneity of ASD have been well-recognized; however, genetic substrates for endophenotypes that constitute phenotypic heterogeneity are not yet known. In the present study, we compiled data from the Autism Genetic Resource Exchange, which contains the demographic and detailed phenotype information of 11,961 individuals. Notably, the whole-genome sequencing data available from MSSNG and iHART for 3833 individuals in this dataset was used to perform an endophenotype-wide association study. Using a linear mixed model, genome-wide association analyses were performed for 29 endophenotype scores and 0.58 million common variants with variant allele frequency ≥ 5%. We discovered significant associations between 9 genetic variants and 6 endophenotype scores comprising neurocognitive development and severity scores for core symptoms of ASD at a significance threshold of p < 5 × 10–7. Of note, the Stereotyped Behaviors and Restricted Interests total score in Autism Diagnostic Observation Schedule Module 3 was significantly associated with multiple variants in the VPS13B gene, a causal gene for Cohen syndrome and a candidate gene for syndromic ASD. Our findings yielded loci with small effect sizes due to the moderate sample size and, thus, require validation in another cohort. Nonetheless, our endophenotype-wide association analysis extends previous candidate gene discovery in the context of genotype and endophenotype association. As a result, these candidate genes may be responsible for specific traits that constitute core symptoms and neurocognitive function of ASD rather than the disorder itself.

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Striatal transcriptome changes linked to drug‐induced repetitive behaviors

Cited by 10 publications

References 106 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

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

Quantitative trait locus analysis for endophenotypes reveals genetic substrates of core symptom domains and neurocognitive function in autism spectrum disorder

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