Abstract
CLN5 disease is a rare form of late-infantile neuronal ceroid lipofuscinosis (NCL) caused by mutations in the CLN5 gene that encodes a protein whose primary function and physiological roles remains unresolved. Emerging lines of evidence point to mitochondrial dysfunction in the onset and progression of several forms of NCL, offering new insights into putative biomarkers and shared biological processes. In this work, we employed cellular and murine models of the disease, in an effort to clarify disease pathways associated with CLN5 depletion. A mitochondria-focused quantitative proteomics approach followed by functional validations using cell biology and immunofluorescence assays revealed an impairment of mitochondrial functions in different CLN5 KO cell models and in Cln5−/− cerebral cortex, which well correlated with disease progression. A visible impairment of autophagy machinery coupled with alterations of key parameters of mitophagy activation process functionally linked CLN5 protein to the process of neuronal injury. The functional link between impaired cellular respiration and activation of mitophagy pathways in the human CLN5 disease condition was corroborated by translating organelle-specific proteome findings to CLN5 patients’ fibroblasts. Our study highlights the involvement of CLN5 in activation of mitophagy and mitochondrial homeostasis offering new insights into alternative strategies towards the CLN5 disease treatment.
Highlights
Introduction TheNeuronal ceroid lipofuscinoses (NCL) are the most common inherited progressive encephalopathies of childhood characterized by epilepsy, blindness, dementia, motor impairment and premature death
Categorization of mitochondrial differentially expressed proteins (mtDEPs) was performed through the use of Ingenuity Pathway Analysis (IPA)[23]
We identified canonical pathways related to mitochondrial dysfunction and oxidative phosphorylation, whereas among the affected disease and functions, mitochondrial membrane potential, ATP synthase, mitochondrial disorder, modification of reactive oxygen species (ROS), morphology of mitochondria, consumption of oxygen and metabolism of hydrogen peroxide were pinpointed among others
Summary
Neuronal ceroid lipofuscinoses (NCL) are the most common inherited progressive encephalopathies of childhood characterized by epilepsy, blindness, dementia, motor impairment and premature death. Pathological, and molecular criteria, fourteen different forms of NCL have been described so far, associated with nearly 400 mutations The disease exhibits a relatively slowly progressive course advancing further with visual failure, motor and mental decline, ataxia, myoclonus and epilepsy. A recent natural history study of the CLN5 disease highlighted the presence of two groups of patients with different clinical severity defining the conditions for experimental or disease-modifying treatments within the first 3 years of the disease[7], as thereafter, high variability in rate of decline is evident in patients based on mutation type and residual levels of CLN5 protein
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