CSPα in Neurodegenerative Disease
This open access paper discusses the possible role of CSPα expression and function in neurodegeneration. CSPα is connected to mechanisms involved in clearance of the protein aggregates that build up in the brain with age. Toxicity associated with these aggregates is implicated in the onset and progression of neurodegenerative conditions. Since the connection seems connected to cellular quality control mechanisms, it is plausible that manipulation of CSPα expression will be more effective in short-lived species such as mice than in long-lived species such as our own. Short-lived species appear to respond to more readily to upregulation of autophagy and other stress responses that act to maintain the molecular machinery of the cell.
Adult-onset neuronal ceroid lipofuscinosis (ANCL) is an inherited neurodegenerative disease with progressive neuronal dysfunction characterized by neuronal death and lipofuscin deposition in the neuronal or non-neuronal lysosomes. Although mutations in CSPα, encoded in the human DNAJC5 gene, are known to be associated with ANCL, the pathogenic mechanisms involved remain unknown. The most well-studied function of CSPα is its cytoplasmic chaperone function. CSPα is abundant in presynaptic vesicles, interacting with HSC70 to ensure correct protein folding. Mutant CSPα causes loss of palmitoylation, mislocalization, and aggregation of CSPα, which then triggers a series of reactions and destabilizes key proteins related to its function, such as synaptic SNAP-25 proteins and PPT1 proteins. Although the exact mechanism is unknown, certain changes in these proteins contribute to NCL.
In numerous animal and human studies, defects in CSPα have been shown to cause neurodegeneration. In addition to ANCL, Alzheimer's disease, Parkinson's disease, FTD, and Huntington's disease have been shown to be associated with CSPα. Although the mechanisms of these neurodegenerative diseases have not been fully explained, neurodegenerative diseases are often associated with protein misfolding. Further studies have revealed that CSPα is essential for transporting misfolded proteins. CSPα has been shown to be associated with lysosomal degradation. Inadequate lysosomal degradation can lead to abnormal membrane flow and misfolded protein entry into endolysosomes, thus leading to error-prone protein accumulation. Additionally, CSPα has been shown to be involved in misfolding-associated protein secretion, endosomal microautophagy, and unfolded protein response processes, which are known to play important roles in maintaining the stability of misfolded proteins. However, all the relevant mechanisms researches are not detailed enough, and more evidence is required to reveal the deeper molecular mechanisms.