Altered protein secretion in Batten disease

Abstract

The neuronal ceroid lipofuscinoses (NCLs), collectively known as Batten disease, are a group of neurological diseases that affect all ages and ethnicities worldwide. There are 13 different subtypes of NCL, each caused by a mutation in a distinct gene. The NCLs are characterized by the accumulation of undigestible lipids and proteins in various cell types. This leads to progressive neurodegeneration and clinical symptoms including vision loss, progressive motor and cognitive decline, seizures, and premature death. These diseases have commonly been characterized by lysosomal defects leading to the accumulation of undigestible material but further research on the NCLs suggests that altered protein secretion may also play an important role. This has been strengthened by recent work in biomedical model organisms, including Dictyostelium discoideum, mice, and sheep. Research in D. discoideum has reported the extracellular localization of some NCL-related proteins and the effects of NCL-related gene loss on protein secretion during unicellular growth and multicellular development. Aberrant protein secretion has also been observed in mammalian models of NCL, which has allowed examination of patient-derived cerebrospinal fluid and urine for potential diagnostic and prognostic biomarkers. Accumulated evidence links seven of the 13 known NCL-related genes to protein secretion, suggesting that altered secretion is a common hallmark of multiple NCL subtypes. This Review highlights the impact of altered protein secretion in the NCLs, identifies potential biomarkers of interest and suggests that future work in this area can provide new therapeutic insight.

Safeguarding Lysosomal Homeostasis by DNAJC5/CSPα-Mediated Unconventional Protein Secretion and Endosomal Microautophagy

“…Given that many CLN-associated mutations known to date are recessive loss-of-function alleles that cause a deficiency in lysosomal degradation, our study underscores a special class of CLN mutations that cause abnormal flow of membranes and misfolded proteins into endolysosomes, which dominantly disrupts lysosomal function. Our model is also consistent with recent studies implicating several other CLN proteins in unconventional protein secretion ( Huber, 2021 ).…”

Identification of substrates of palmitoyl protein thioesterase 1 highlights roles of depalmitoylation in disulfide bond formation and synaptic function

“…The palmitoylated cysteines identified in the other synaptic adhesion molecules are also known to mediate intra- or intermolecular interactions via disulfide bonds [ 55 ]. Secreted endogenous PPT1 enzyme activity was detected in the media of WT primary neuronal cultures ( Fig 4D ), suggesting that PPT1 could act in the extracellular space [ 56 ]. Decreased colocalization of CADM2 and SYPH in PPT1 KO neurons ( Fig 4E and 4F ) suggests that altered depalmitoylation of synaptic adhesion molecules impacts subsynaptic localization.…”

The Cellular and Developmental Roles of Cullins, Neddylation, and the COP9 Signalosome in Dictyostelium discoideum

“…Importantly, D. discoideum is genetically tractable and a variety of expression constructs have been generated to facilitate studies on protein localization and function ( Levi et al, 2000 ; Kuspa, 2006 ; Veltman et al, 2009 ; Faix et al, 2013 ; Müller-Taubenberger and Ishikawa-Ankerhold, 2013 ; Friedrich et al, 2015 ; Yamashita et al, 2021 ). For these and other reasons, it has also been used as a high-throughput biomedical model for studying variety of human diseases ( Huber, 2021 ; Kirolos et al, 2021 ; Mathavarajah et al, 2021 ; Pain et al, 2021 ).…”