DNAJB6 suppresses alpha-synuclein induced pathology in an animal model of Parkinson's disease

Arkan, Sertan; Ljungberg, Mårten; Kirik, Deniz; Hansen, Christian

doi:10.1016/j.nbd.2021.105477

Cited by 20 publications

(20 citation statements)

References 43 publications

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“…5 D and E). Taken together, our results establish that the same group of co-chaperones from the DNAJB family that reduce poly-Q, α-synuclein, and TDP-43 aggregation [ 1 , 2 , 10 , 25 ], also strongly reduce the formation of insoluble poly-GA aggregates. These findings suggest that current efforts to harness the activity of cellular chaperone networks to target neuropathological aggregates may be used to target poly-GA aggregates in c9FTD/ALS patients [ 17 , 88 , 99 ].…”

Section: Resultssupporting

confidence: 67%

“…This work also reveals a novel role of the DNAJB family of co-chaperones that have been previously shown to reduce poly-Q and α-synuclein aggregation [ 1 , 19 , 25 , 79 ] and modulate their pathology in animal models of Parkinson’s disease and Huntington’s disease [ 2 , 38 ], in strongly reducing the formation of insoluble poly-GA aggregates (Fig. 5 A and B).…”

Section: Discussionmentioning

confidence: 55%

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Proximity proteomics of C9orf72 dipeptide repeat proteins identifies molecular chaperones as modifiers of poly-GA aggregation

Liu

Morderer

Wren

et al. 2022

acta neuropathol commun

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The most common inherited cause of two genetically and clinico-pathologically overlapping neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is the presence of expanded GGGGCC intronic hexanucleotide repeats in the C9orf72 gene. Aside from haploinsufficiency and toxic RNA foci, another non-exclusive disease mechanism is the non-canonical translation of the repeat RNA into five different dipeptide repeat proteins (DPRs), which form neuronal inclusions in affected patient brains. While evidence from cellular and animal models supports a toxic gain-of-function of pathologic poly-GA, poly-GR, and poly-PR aggregates in promoting deposition of TDP-43 pathology and neurodegeneration in affected brain areas, the relative contribution of DPRs to the disease process in c9FTD/ALS patients remains unclear. Here we have used the proximity-dependent biotin identification (BioID) proximity proteomics approach to investigate the formation and collective composition of DPR aggregates using cellular models. While interactomes of arginine rich poly-GR and poly-PR aggregates overlapped and were enriched for nucleolar and ribosomal proteins, poly-GA aggregates demonstrated a distinct association with proteasomal components, molecular chaperones (HSPA1A/HSP70, HSPA8/HSC70, VCP/p97), co-chaperones (BAG3, DNAJA1A) and other factors that regulate protein folding and degradation (SQSTM1/p62, CALR, CHIP/STUB1). Experiments in cellular models of poly-GA pathology show that molecular chaperones and co-chaperones are sequestered to the periphery of dense cytoplasmic aggregates, causing depletion from their typical cellular localization. Their involvement in the pathologic process is confirmed in autopsy brain tissue, where HSPA8, BAG3, VCP, and its adapter protein UBXN6 show a close association with poly-GA aggregates in the frontal cortex, temporal cortex, and hippocampus of c9FTLD and c9ALS cases. The association of heat shock proteins and co-chaperones with poly-GA led us to investigate their potential role in reducing its aggregation. We identified HSP40 co-chaperones of the DNAJB family as potent modifiers that increased the solubility of poly-GA, highlighting a possible novel therapeutic avenue and a central role of molecular chaperones in the pathogenesis of human C9orf72-linked diseases.

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Section: Resultssupporting

confidence: 67%

Section: Discussionmentioning

confidence: 55%

Proximity proteomics of C9orf72 dipeptide repeat proteins identifies molecular chaperones as modifiers of poly-GA aggregation

Liu

Morderer

Wren

et al. 2022

acta neuropathol commun

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“…And the immune dysregulation can cause the upregulation of inflammatory cytokines to initiate a cascade of pro-inflammatory signaling that ultimately result in the neurotoxicity related to Parkinson’s disease [6]. Thus, the RNA editing event may also involve in these functions through its effects on the host gene and multiple other genes, especially on the five PD-related genes including EIF2AK2 [13], MCL1 [15], P4HB [50], DNAJB6 [51], and APP [52].…”

Section: Resultsmentioning

confidence: 99%

The Potential Regulation of A-to-I RNA editing on Genes in Parkinson’s Disease

Xue

Qin

et al. 2022

Preprint

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Parkinson's disease (PD), the second most common neurodegenerative disorder, was characterized by alpha-synuclein pathology and dopaminergic neuron degeneration. In previous studies, multiple genes have been demonstrated to involve in the regulations of these two processes, including EIF2AK2, AGO2, MCL1, EEF1A1, and AIMP2. The molecular mechanisms to mediate the transcript diversity of these genetic biomarkers were important to understand neurodegenerative pathogenesis and helpful for treatment design. In this study, we analyzed 372 PD patients to identify 9,897 A-to-I RNA editing events probably responsible for the controls of 6,286 genes. Due to the most potentially trans-regulatory associations between RNA editing events and genes, we tried to explain one possible pathway from the view of disturbed miRNA regulations on genes due to A-to-I RNA editing events. Specifically, we identified 72 RNA editing events probably interfering in miRNA regulations on their host genes, eight RNA editing events possibly altering miRNA competitions between their host genes and 1,146 other genes, and one RNA editing event modifying miRNA seed regions to potentially disturb its regulations on four genes. All the analyses revealed 25 RNA editing biomarkers in Parkinson's pathogenesis through probably interfering in miRNA degradations on 133 PD-related genes.

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“…This is the case with DnaJB1, Hsp70, and the Apg2 nucleotide exchange factor that convert cytotoxic fibrils to nontoxic monomeric α-syn in an ATP-dependent manner ( 160 ). Another molecular cochaperone, DnaJB6, has been shown to suppress the aggregation of seeded α-syn in cells and in animal models of PD ( 146 , 161 , 162 , 163 ). Different chaperone proteins can bind to different populations of misfolded α-syn.…”

Section: Parkinson's Diseasementioning

confidence: 99%

Protein interaction networks in neurodegenerative diseases: From physiological function to aggregation

Calabrese

Molzahn

Mayor

2022

Journal of Biological Chemistry

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DNAJB6 suppresses alpha-synuclein induced pathology in an animal model of Parkinson's disease

Cited by 20 publications

References 43 publications

Proximity proteomics of C9orf72 dipeptide repeat proteins identifies molecular chaperones as modifiers of poly-GA aggregation

Proximity proteomics of C9orf72 dipeptide repeat proteins identifies molecular chaperones as modifiers of poly-GA aggregation

The Potential Regulation of A-to-I RNA editing on Genes in Parkinson’s Disease

Protein interaction networks in neurodegenerative diseases: From physiological function to aggregation

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