The collection of diseases referred to as Neuronal ceroid lipofuscinoses (NCL) represent the most common inherited pediatric neurodegenerative disorders worldwide. They are characterized by progressive cerebral atrophy, epileptic seizures, progressive cognitive and motor decline, visual failure, and premature death (1). Fourteen subtypes of NCL exist, and each subtype is associated with a distinct ceroid lipofuscinosis neuronal (CLN) mutated gene (2). The CLN genes encode various cytosolic, lysosomal, and integral membrane proteins. Mutations in CLN genes cause the accumulation of autofluorescent lipoprotein aggregates, called ceroid lipofuscin, in neurons and other cell types outside the central nervous system. Unfortunately, NCLs are mainly incurable diseases and only one FDA-approved treatment (targeting CLN2) exists (3). Therefore, the exploration of new potential molecular targets is needed for therapeutic purposes.

Many genes present in the network have a known association with NCL as represented in the QKG, namely CLN3, CLN5, CLN6, CLN8, CTSD, CTSF, DNAJC5, MFSD8, PPARA, PPT1, and TPP1 proteins which typically localize to the lysosomal lumen/membrane or ER membrane/golgi complex.

While many of the genes gave have established functions, such as CLN8 (ER-golgi protein transport), CTSD (aspartyl endopeptidase), CTSF (cysteine protease), DNAJC5 (co-chaperone protein), PPARA (transcription factor), PPT1(protein thioesterase), and TPP1 (serine protease), the functions of two CLNs, CLN3 and MFSD8 (also known as CLN7) have not been fully described. The majority of the NCL-associated genes are involved in critical cellular processes such as endocytosis, exocytosis, ER-Golgi protein trafficking, autophagosome and lysosome formations and in autophagic process in general (2). CLN3 has recently been implicated in regulation of the cytoskeleton, ion channels, and trafficking, and loss-of-function mutations can lead to Juvenile NCL (also referred to as Batten disease or CLN3 disease) (4). Similarly, PPT1 (palmitoyl-protein thioesterase-1) has a recently established role in lysosomal calcium homeostasis in a mouse model and inactivating mutations lead to CLN1 disease (5). DNAJC5 plays a role in membrane trafficking and protein folding, and has been shown to have anti-neurodegenerative properties (QKG) and may be involved in autophagy through its regulation of dynamin-1 (2). Mutations in (CLN4 a.k.a Parry disease) lead to the disease's only autosomal dominantly transmitted adult-onset form.

The network contains an additional 20 genes predicted to be associated with NCL: ACLY, AIFM1, BACH1, CAB39L, CLPP, DAP3, H2AX, HK2, IGFR1, KDM5A, LDHB, LONP1, MCU, NUBPL, OMA1, PTCD1, RB1, STK11, YARS2, and ZNF746. None of these currently have known connections with NCL directly in our QKG. However, many have direct or indirect molecular connections with abnormal lysosomal storage, or to autophagy (lysosomal degradation pathway) dysregulation. Defects in autophagy are linked to many neurodegenerative pathologies, backed by recent evidence indicating its prominent role in NCL (2). A few examples in that context are discussed briefly below.

Proper regulation of autophagy is shown to be beneficial in many biological processes including oocyte maturation. During oocyte maturation, ACLY is selectively degraded by autophagy, and this degradation controls ATP citrate lyase levels, whereas a reduced level of autophagy is observed in human granulosa cells from women of advanced maternal age (6). ACLY generates cytosolic Acetyl-CoEnzyme A from citrate, and cytosolic Acetyl CoEnzyme A is known to be a central metabolic regulator of autophagy (7). BACH1 is a known transcriptional repressor of the transcription factor NFE2L2 (8), a regulator of autophagy gene expression relevant to Alzheimer disease, as shown in mouse (9). Furthermore, Bach1 inhibition has been proposed as a therapy for Parkinson's Disease (8). DAP3 is a mitochondrial ribosomal component involved in mitochondrial homeostasis is essential to autophagy induction (10). HK2 is a glycolytic enzyme recently shown to play a key role in autophagy activation under hypoxic conditions via inhibition of mTORC1. Its knockdown via siRNA inhibited autophagy in a cancer cell line model (11). Finally, PTCD1 (a mitochondrial protein) and STK11 (a serine/threonine kinase) participate in the regulation of autophagy (QKG).


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9. Pajares M et al. (2016) Autophagy 12(10):1902-1916. PMID: 27427974
10. Xiao, L, et al. (2015) J Biol Chem 290(41):24961-74. PMID: 26306039
11. Ikeda S, et al. (2020) Cancer Sci. (11):4088-4101. PMID: 32790954