DnaJC7 in Amyotrophic Lateral Sclerosis

Dilliott, Allison A.; Andary, Catherine M; Stoltz, Meaghan; Petropavlovskiy, Andrey A.; Farhan, Sali M.K.; Duennwald, Martin L.

doi:10.3390/ijms23084076

Cited by 19 publications

(11 citation statements)

References 80 publications

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“…DnaJC7 contains a C-terminal J domain and tetratricopeptide repeat (TPR) domains (Dilliott et al, 2022). The TRP domains are predicted to interact with Hsp90 and Hsp70 and may facilitate the flow of client proteins from Hsp70s to Hsp90s (Assimon et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

Cysteine String Protein alpha in Extracellular Vesicle Subtypes: a Proteomic Analysis

Nogueira de Almeida,

Armstrong,

Dufour

et al. 2023

Preprint

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Cysteine string protein (CSPα /DnaJC5) is a presynaptic J-domain protein (JDP) that prevents neurodegeneration. CSPα/DnaJC5 is reported to facilitate export of distinct, highly oligomeric, disease-causing proteins in addition to wild-type TDP-43, tau and α-synuclein. Yet, detailed mechanistic knowledge of the full CSPα/DnaJC5 secreted proteome is lacking. Understanding the CSPα/DnaJC5 export pathway has implications for a growing number of neurodegenerative diseases. In humans, Leu115Arg or Leu116deletion mutations cause adult-onset neuronal ceroid lipofusinosis (ANCL), a rare neurodegenerative disorder. In the present study, we examined extracelular vesicles (EVs) released from CSPα/DnaJC5 expressing cells. Cells are known to secrete many types of EVs of different sizes and origins into the extracellular space. EV subpopulations were separated by their sedimentation speed and subjected to proteomic analysis. We find that CSPα/DnaJC5 and the CSPα/DnaJC5 mutants, Leu115Arg or Leu116del are enriched in multiple EV subpopulations. The exported protein profile is determined by proteomics. We report that several other J-domain proteins (JDPs), such as DnaJC7, DnaJA1 and DnaJA2 are exported and speculate that export of JDPs may facilitate the secretion of diverse client proteins. Our work provides a platform for further inquiry into the role of secreted CSPα/DnaJC5 and other JDPs in proteostasis.

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Section: Resultsmentioning

confidence: 99%

Cysteine String Protein alpha in Extracellular Vesicle Subtypes: a Proteomic Analysis

Nogueira de Almeida,

Armstrong,

Dufour

et al. 2023

Preprint

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“…DnaJC7 mutations cause dominantly inherited Amyotrophic Lateral Sclerosis (ALS) 24 . 17 mutations have been identified that are distributed across all domains of DnaJC7 (Figure 5C).…”

Section: Disease-associated Dnajc7 Mutations Differentially Modulate ...mentioning

confidence: 99%

“…Instead of destabilizing DnaJC7, these mutations exhibit gain-of-function effects likely through dysregulation of interactions within the chaperone network. Disease-associated mutations occur in both DnaJC7 and DnaJB6 24,30,31 . This suggests that DnaJB6, DnaJC7 and other JDPs are not functionally redundant.…”

Section: Disease-associated Mutations Of Dnajc7 Differentially Affect...mentioning

confidence: 99%

“…These mutations, ranging from missense to stop-gain mutants, inhibit the ability of the JDPs to bind clients or transfer them to Hsp70 and produce different disease pathologies. Recently, a series of protein truncating variants and missense mutations to the DnaJC7 gene have been identified as causal for ALS 24 . The missense mutations were found across all domains of DnaJC7, with most localized to the helix-turn-helix loops on the TPR motifs.…”

Section: Disease-associated Mutations Of Dnajc7 Differentially Affect...mentioning

confidence: 99%

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DnaJC7 specifically regulates tau seeding

Pérez

Sanders

Mendoza-Oliva

et al. 2023

Preprint

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Neurodegenerative tauopathies are caused by accumulation of toxic tau protein assemblies. This appears to involve template-based seeding events, whereby tau monomer changes conformation and is recruited to a growing aggregate. Several large families of chaperone proteins, including Hsp70s and J domain proteins (JDPs) cooperate to regulate the folding of intracellular proteins such as tau, but the factors that coordinate this activity are not well known. The JDP DnaJC7 binds tau and reduces its intracellular aggregation. However, it is unknown whether this is specific to DnaJC7 or if other JDPs might be similarly involved. We used proteomics within a cell model to determine that DnaJC7 co-purified with insoluble tau and colocalized with intracellular aggregates. We individually knocked out every possible JDP and tested the effect on intracellular aggregation and seeding. DnaJC7 knockout decreased aggregate clearance and increased intracellular tau seeding. This depended on the ability of the J domain (JD) of DnaJC7 to bind to Hsp70, as JD mutations that block binding to Hsp70 abrogated the protective activity. Disease-associated mutations in the JD and substrate binding site of DnaJC7 also abrogated its protective activity. DnaJC7 thus specifically regulates tau aggregation in cooperation with Hsp70.

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“…In conclusion, there is intense, ongoing research on ALS, which is leading to interesting findings [ 10 ].…”

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confidence: 99%