The converging roles of Batten disease proteins in neurodegeneration and cancer

Abstract

Summary Epidemiological studies have reported an inverse correlation between cancer and neurodegenerative disorders, and increasing evidence shows that similar genes and pathways are dysregulated in both diseases but in a contrasting manner. Given the genetic convergence of the neuronal ceroid lipofuscinoses (NCLs), a family of rare neurodegenerative disorders commonly known as Batten disease, and other neurodegenerative diseases, we sought to explore the relationship between cancer and the NCLs. In this review, we survey data from The Cancer Genome Atlas and available literature on the roles of NCL genes in different oncogenic processes to reveal links between all the NCL genes and cancer-related processes. We also discuss the potential contributions of NCL genes to cancer immunology. Based on our findings, we propose that further research on the relationship between cancer and the NCLs may help shed light on the roles of NCL genes in both diseases and possibly guide therapy development.

Combination of Antimalarial and CNS Drugs with Antineoplastic Agents in MCF-7 Breast and HT-29 Colon Cancer Cells: Biosafety Evaluation and Mechanism of Action

“…CQ is known to inhibit this enzyme [ 18 , 19 ]. The activity of PPT1 in cancer cells involves the depalmitoylation of the V0a1 subunit of v-ATPase, which facilitates the v-ATPase assembly on the lysosomal membrane [ 34 ]. Then, the V1 subunit of v-ATPase interacts with Ragulator, enabling the formation of the mTORC1 complex on the lysosome and activating mTORC1.…”

“…Then, the V1 subunit of v-ATPase interacts with Ragulator, enabling the formation of the mTORC1 complex on the lysosome and activating mTORC1. This activation induces protein synthesis and inhibits the autophagic process [ 34 ]. PPT1 can also remove palmitate from palmitoylated proteins prior to their degradation in the lysosome.…”

“…PPT1 can also remove palmitate from palmitoylated proteins prior to their degradation in the lysosome. PPT1 inhibition impairs the depalmitoylation of the V0a1 subunit of v-ATPase, disrupting the assembly of v-ATPase and causing lysosomal deacidification [ 34 ]. Furthermore, the interaction between the V0a1 subunit of v-ATPase and Ragulator is lost, causing the inhibition of mTORC1, which inhibits protein synthesis and stops cell proliferation and tumor growth, and impairs autophagy [ 34 ].…”

“…PPT1 inhibition impairs the depalmitoylation of the V0a1 subunit of v-ATPase, disrupting the assembly of v-ATPase and causing lysosomal deacidification [ 34 ]. Furthermore, the interaction between the V0a1 subunit of v-ATPase and Ragulator is lost, causing the inhibition of mTORC1, which inhibits protein synthesis and stops cell proliferation and tumor growth, and impairs autophagy [ 34 ]. In this work, we hypothesize if the proposed drug combinations can inhibit PPT1 enzyme.…”

The Dictyostelium Model for Mucolipidosis Type IV

“…Dictyostelium is a well-established model to study neurodegenerative and lysosomal disease ( Annesley and Fisher 2009 ; Maniak, 2011 ; Annesley et al, 2014 ; Martín-González et al, 2021 ). This model organism has been extensively employed to study neuronal ceroid lipofuscinosis (NCL) ( Huber, 2020 ), a group of lysosomal diseases linked to mutations in the genes, CLN1–CLN8 and CLN10–CLN14 ( Yap et al, 2021 ). Therefore, Dictyostelium is an ideal model to study lysosomal disorders and mucolipin function.…”