DNAJC10 (also known as ERdj5) is a member of the DnaJ/Hsp40 family of molecular chaperones. DNAJC10 is primarily localized to the endoplasmic reticulum (ER) where it plays critical roles in protein folding, quality control, and ER-associated degradation (ERAD). This chaperone has emerged as an important player in neurodegenerative diseases characterized by protein misfolding and ER stress["@cunningham2018"].
Function
DNAJC10/ERdj5 possesses multiple domains and functions:
J Domain: Binds to Hsp70 family proteins and stimulates their ATPase activity
Client Binding Domain: Recognizes and binds to misfolded proteins
Thioredoxin Domains: Contains two thioredoxin-like domains with redox activity
ER Localization: Contains an ER retention signal (KDEL or RDEL)
ERAD Function: Facilitates retrotranslocation of misfolded proteins for degradation
Molecular Mechanism
DNAJC10/ERdj5 functions as a specialized ERAD co-chaperone:
Substrate recognition: The J domain and client-binding region identify misfolded proteins in the ER lumen
Hsp70 recruitment: DNAJC10 recruits BiP (GRP78) through J domain-mediated stimulation
Redox regulation: Thioredoxin domains maintain substrate redox state for proper folding
Retrotranslocation: Facilitates transfer of substrates to the Derlin channel
Dislocation: Co-operates with EDEM and PDI for substrate extraction
Protein Domain Structure
Role in Neurodegenerative Diseases
Alzheimer's Disease
ER Stress Response: DNAJC10 helps manage ER stress induced by [Aβ](/proteins/amyloid-beta) accumulation[@hashimoto2019]
Protein Quality Control: Enhances clearance of misfolded proteins through ERAD
Calcium Homeostasis: ER chaperone function affects calcium signaling
Synaptic Protection: May protect synapses from protein aggregation
Parkinson's Disease
[α-Synuclein](/proteins/alpha-synuclein) Clearance: DNAJC10 may facilitate clearance of misfolded α-synuclein[@soto2012]
ER Stress: PD-associated proteins induce ER stress that DNAJC10 helps manage
Dopaminergic Neuron Vulnerability: The [unfolded protein response](/entities/unfolded-protein-response) in dopaminergic [neurons](/entities/neurons)
ALS
Protein Aggregation: DNAJC10 helps manage aggregation-prone proteins in ALS
ERAD Enhancement: May enhance clearance of mutant SOD1 and [TDP-43](/mechanisms/tdp-43-proteinopathy)
Motor Neuron Stress: ER stress is a key feature of ALS pathogenesis
Pathogenic Mechanisms
ER Stress-Mediated Apoptosis
Chronic ER stress triggers the unfolded protein response (UPR):
IRE1 pathway: Pro-apoptotic splicing of XBP1
PERK pathway: Translation repression, CHOP induction
ATF6 pathway: Pro-apoptotic gene expression
Protein Aggregation
DNAJC10 deficiency contributes to:
Impaired clearance of aggregation-prone proteins
Increased load on proteostasis systems
Formation of toxic oligomers
Calcium Dysregulation
ER chaperone dysfunction affects:
ER calcium store maintenance
Calcium signaling abnormalities
Mitochondrial calcium overload
Therapeutic Implications
Drug Development
ERAD Enhancers: Compounds that enhance ERAD function are being explored
Chaperone Co-inducers: Small molecules that upregulate DNAJC10 expression
Protein Aggregation Inhibitors: Combination approaches targeting multiple pathways
Research Directions
Biomarkers: DNAJC10 expression as a marker of ER stress
Genetic Studies: DNAJC10 polymorphisms and disease risk
Therapeutic Targeting: Developing modulators of DNAJC10 function
Expression Patterns
DNAJC10 shows regulated expression:
Brain Regions: Expressed in [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), and various brain regions
Cellular Localization: ER lumen, with some nuclear localization reported
Stress Induction: Expression is upregulated by ER stress conditions
Interactions
DNAJC10 interacts with multiple proteins:
BiP/GRP78: Major ER Hsp70 that cooperates with DNAJC10
Derlins: Components of the ERAD retrotranslocation channel
EDEM: ER degradation-enhancing α-mannosidase-like protein
PDI: Protein disulfide isomerase family members
SEL1L: ERAD adaptor protein
OS-9: ERAD lectin for misfolded glycoproteins
Animal Models
Knockout Models
DNAJC10 knockout mice show:
Embryonic lethality (some alleles)
ER stress accumulation
Impaired protein quality control
Overexpression Models
DNAJC10 overexpression provides:
Enhanced ERAD function
Protection against proteotoxic stress
Improved protein clearance
Clinical Significance
Genetic Associations
DNAJC10 polymorphisms have been associated with:
AD risk in some populations
PD progression
ALS age of onset
Therapeutic Targets
DNAJC10 is a promising therapeutic target:
Small molecule inducers: Upregulate DNAJC10 expression
ERAD modulators: Enhance substrate clearance
Chaperone agonists: Stabilize DNAJC10 function
See Also
[ER Stress](/mechanisms/er-stress)
[Unfolded Protein Response](/mechanisms/unfolded-protein-response) ER-Associated Degradation