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.

Keywords: Dictyostelium discoideum; Batten disease; Cerebrospinal fluid; Model system; Neuronal ceroid lipofuscinosis; Secretion; Urine.

Fig. 1.

The life cycle of Dictyostelium discoideum. Microscopy images showing the development of D. discoideum cells when applying two commonly used experimental setups, i.e. cells adhered to Petri dishes and submerged in a development buffer (top), and cells adhered to nitrocellulose membranes soaked in development buffer (bottom). During the vegetative, i.e. growth, phase of the life cycle, amoebae internalize their food source using phago- or pinocytosis and undergo mitotic cell division. Upon food depletion (onset of starvation), cells stop dividing and initiate a developmental sequence that begins with secretion of cAMP, which functions as a chemoattractant to stimulate cellular adhesion and the formation of multicellular mounds. A mound then undergoes a series of morphological changes to form a slug that migrates on the substratum in response to light and temperature stimuli. Cells within the slug terminally differentiate into either stalk or spores that form the mature fruiting body. When a food source becomes available, the spores germinate, thereby allowing the cells to restart the life cycle. Notice: Cells submerged in development buffer within Petri dishes do not progress past the mound stage. Scale bars: 250 µm (Petri dishes), 1000 µm (nitrocellulose membrane). A modified version of this figure was previously published in Huber et al. (2021).

Fig. 2.

Mechanisms regulating Cln5 secretion in D. discoideum. Cln5 is glycosylated in the ER and trafficked to the CV system prior to secretion. Cln3 localizes to the Golgi complex and CV system. Cln3 also localizes to the late endosome/lysosome, as does Mfsd8. Secretion of Cln5 is regulated by Cln3 and Mfsd8 (i.e. loss of Cln3 or Mfsd8 increases Cln5 secretion), as well as autophagy (autophagy inhibition decreases Cln5 secretion). N-Glyc, N-glycosylation.

Fig. 3.

Protein secretion regulated by Cln3 in D. discoideum. Cln3 localizes to the late endosome/lysosome, together with Tpp1F and CtsD. Tpp1F also localizes to the ER and Golgi complex, and binds GPHR. For secretion via the conventional pathway, proteins are transported via the ER and Golgi complex, where they are packaged into vesicles prior to secretion. The alternative unconventional pathway involves GRASP and the CV system. Cln3 localizes to both the Golgi complex and CV system to regulate protein secretion via these pathways. Loss of cln3 increases the secretion of AprA and CfaD during growth, and Tpp1F, Cln5, CtsD, CprD, CprE, CprF, CprG, CtsB, NagB, and CadA during aggregation. Loss of cln3 decreases the secretion of CmfA during growth, and CprA and CprB during aggregation. Loss of cln3 increases the extracellular activity of beta-glucosidase, alpha-mannosidase, Nag, Tpp1, and CtsD during aggregation. Cpr, cysteine proteinase; GPHR, Golgi pH regulator (officially known as Gpr89); GRASP, Golgi reassembly-stacking protein (officially known as GrpA); N-Glyc, N-glycosylation; Tpp1F, tripeptidyl peptidase 1F.