Decreased sensitivity of palmitoyl protein thioesterase 1-deficient neurons to chemical anoxia

Abstract

Infantile CLN1 disease, also known as infantile neuronal ceroid lipofuscinosis, is a fatal childhood neurodegenerative disorder caused by mutations in the CLN1 gene. CLN1 encodes a soluble lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1), and it is still unclear why neurons are selectively vulnerable to the loss of PPT1 enzyme activity in infantile CLN1 disease. To examine the effects of PPT1 deficiency on several well-defined neuronal signaling and cell death pathways, different toxic insults were applied in cerebellar granule neuron cultures prepared from wild type (WT) and palmitoyl protein thioesterase 1-deficient (Ppt1−/−) mice, a model of infantile CLN1 disease. Glutamate uptake inhibition by t-PDC (L-transpyrrolidine-2,4-dicarboxylic acid) or Zn2+-induced general mitochondrial dysfunction caused similar toxicity in WT and Ppt1−/− cultures. Ppt1−/− neurons, however, were more sensitive to mitochondrial complex I inhibition by MPP+ (1-methyl-4-phenylpyridinium), and had significantly decreased sensitivity to chemical anoxia induced by the mitochondrial complex IV inhibitor, sodium azide. Our results indicate that PPT1 deficiency causes alterations in the mitochondrial respiratory chain.

Clinical features of two Japanese siblings of neuronal ceroid lipofuscinosis type 1 (CLN1) complicated with TypeⅡ diabetes mellitus

“…Acceleration of endocytosis through lipid rafts, abnormal autophagy, and mitochondrial dysfunction has been observed in cells derived from CLN1 patients. In the PPT1 −/− mouse model, PPT1 −/− neurons, compared to wild-type neurons, are more vulnerable to complex I inhibition by 1-methyl-4-phenylpyridinium (MPP), but less sensitive to complex IV inhibition by sodium azide, indicating that PPT1 deficiency causes alterations in the mitochondrial respiratory chain [ 18 ].…”

Deacylases—structure, function, and relationship to diseases

“…Additionally, some studies have demonstrated that PPT1 can functionally regulate mitochondrial complexes I and IV to influence mitochondrial respiratory chain activity [81]. This phenomenon is speculated to be associated with protein levels of key mitochondrial components such as ATP synthase F0 complex and cytochrome c oxidase subunits [82].…”

Protein palmitoylation and its pathophysiological relevance

“…For instance, the mitochondrial ATP synthase F1 complex has been found to be a bona fide substrate of PPT1, and its depalmitoylation is indispensable for its proper localization (Annina et al, 2008). In addition, PPT1 regulates the function of complexes I and IV of the mitochondrial electron transport chain and thus influences the mitochondrial respiratory chain (Meyer et al, 2017). PPT1 also participates in the regulation of V‐ATPase function by affecting its localization to the PM and thus tunes the level of cellular autophagy (Bagh et al, 2017).…”