Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• DNAJC5 encodes cysteine string protein-α (CSPα), an endolysosomal cochaperone involved in synaptic integrity and the autophagy/lysosomal pathway (ALP).
• Elevated CSPα expression in microglia suggests cell-type-specific roles in brain proteostasis, particularly relevant to Alzheimer's disease (AD).

Purpose of the Study:

• To investigate CSPα-dependent proteostasis.
• To explore the role of CSPα in Alzheimer's disease (AD) pathogenesis.

Main Methods:

• Generated transcriptome and proteomic data from human cell lines (neuronal, astrocyte, microglial) overexpressing wild-type (WT) and mutant CSPα.
• Analyzed patient-derived iPSCs with mutant CSPα and CRISPR-corrected controls, differentiated into cortical neurons.
• Integrated proteomic data from human brain tissue of CSPα mutation carriers and healthy controls.

Main Results:

• Mutant CSPα carriers exhibit CSPα aggregates and autophagic dysfunction, replicating findings in AD brain tissue.
• Proteomic and transcriptomic analyses reveal altered ALP proteins, inflammation-associated proteins (especially in microglia), and differentially expressed genes related to microglia and interferon response.
• Mutant CSPα expression leads to protein aggregation, depalmitoylation, and altered autophagic flux in neuronal and microglial cell lines.

Conclusions:

• Mutant CSPα induces cell-type-specific aggregation and dysregulates proteostatic pathways, with implications for AD-related proteinopathies.
• Further multi-omics analysis will clarify cell-type-specific CSPα-associated neurodegenerative pathways.
• Future research will elucidate CSPα's precise regulation of AD proteostasis.