Background
The endolysosomal and autophagic pathways of degradation
Lysosomal acidification
The endosome-lysosome and autophagosome-lysosome fusion
CLN gene mutations and their differential pathologic manifestations in various NCLs
Mutant Gene | NCL Disease | Encoded Protein | Classification and protein size | Posttranslational modification | Subcellular localization | Function | Interactions |
---|---|---|---|---|---|---|---|
CLN1
| Infantile NCL (CLN1-disease) | Palmitoyl protein thioesterase 1 (PPT1) | soluble protein, 306 aa | N-gly M6P | Lysosomal lumen, extralysosomal vesicules, extracellular, presynaptic areas in neurons | Palmitoy-protein lthioesterase | S-acetylated proteins (GAP43, rhodopsin, saposin D) |
CLN2
| Late infantile NCL | Tripeptidyl peptidase 1 (TPP1) | soluble protein, 563 aa | N-gly M6P | Lysosomal lumen | Serine protease | CLN3, CLN5 |
CLN3
| Juvenile NCL, Batten disease | CLN3/Batenin | 6 TM protein, 438 aa | N-gly farnesylated phosphorylated | Late endosomal/lysosomal membrane, presynaptic vesicles | Unknown / predicted: pH regulation and modulation of vesicular trafficking and fusion | Hook1, kinesin-2, CLN5, Na+, K + ATPase, Rab7, fodrin |
CLN4
| Kuffs disease | Cysteine-string protein alpha (CSPα), DNAJC5 | soluble protein, 198 aa | Palmitoylated | Cytosolic, vesicular membranes | Hsc70 co-chaperone involved in exocytosis and endocytosis | CSPα, SNAP-25, myosin IIB, calsenilin, DHHC17, dynamin-1, syntaxin, Gαs, Rab3b, synaptotagmin 9, Hsp70, Hsp40, Hsp90, HIP, HOP, SGT |
CLN5
| CLN5 disease | – | soluble protein, 407 aa | N-gly M6P | Lysosomal lumen | Unknown / predicted: modulation of vesicular trafficking | PPT1/CLN1, TPP1/CLN2, CLN3, CLN6, CLN8 |
CLN6
| CLN6 disease | CLN6-protein | 7 TM protein, 311 aa | None | ER-membrane (transmembrane) | Unknown | CLN5, CLN6 CRMP-2 |
CLN7
| Turkish variant of late-infantile NCL | MFSD8 | 12 TM protein, 518 aa | N-gly proteolytic cleaved | Lysosomal membrane | Predicted transmembrane transporter function predicted | AP-1, cathepsin L |
CLN8
| NCL 8 |
CLN8
| 5 TM protein, 286 aa | None | ER-membrane (transmembrane) | Unknown, predicted: to aid in the maturation of lysosomal proteins by transporting them from the ER to the Golgi complex, predicted regulation in lipid metabolism, | CLN5, CLN8, syntaxin 8, VAPA, GATE16, AGA, ARSA, ARSB, ARSG, CTBS, CTSA, CTSB, CTSD, CTSF, CTSZ, DNASE2, GALNS, GGH, GM2A, GNS, GUSB, HPSE, IDS, LIPA, MAN2B1, MAN2B2, MPO, NAGA, NEU1, PCYOX1, PLBD2, PPT1, PPT2, PSAP, RNASET2, SGSH, SIAW, SMPD1, TPP1 |
CLN9
| – | Currently designated as CLN4 | – | – | – | – | – |
CLN10
| Congenital NCL | Cathepsin D (CTSD) | soluble protein, 462 aa | N-gly M6P | Lysosomal lumen | Aspartyl protease | APP, CST3, CTSB, proSAP, and several others |
CLN11
| Unknown | Progranulin and granulins | soluble protein, 593 aa | None | Extracellular | Unknown/ predicted, roles in inflammation, embryogenesis, cell motility and tumorigenesis | MMPs, ADAMs, TGFα receptors, sortilin, ADAMTS-7/ADAMTS-12/perlecan/HDL/COMP, TGNFα receptors, EPHA2 |
CLN12
| Unknown | ATPase 13A2, KRPPD, PARK9, HSA9947, RP-37C10.4 | 10 TM protein, 1180 aa | None | Lysosomal membrane | Unknown / predicted regulation of ion homeostasis | ~ 43 vesicular trafficking and synuclein misfolding postulated proteins |
CLN13
| Unknown | Cathepsin F (CTSF) | soluble protein, 484 aa | N-gly M6P | Lysosomal lumen | Unknown / predicted: cysteine protease | CD47 antigen |
CLN14
| Unknown | Potassium channel tetramerization domain-containing protein 7 (KCTD7) | soluble protein, 289 aa | Phosphorylated | Cytosolic, partially associated to membranes | Unknown / predicted modulation of ion channel activity | Cullin-3, KCTD7 |
Mutant Gene | Cells/ tissues | Myoclonus & Seizures | Autofluorescent inclusions | Elevated lysosomal pH | ER Stress | Dysregulated degradation | Cellular dysfunction |
---|---|---|---|---|---|---|---|
CLN1
| Ubiquitously expressed, CNS, brain | X | X | X | X | X | protein response |
CLN2
| Ubiquitously expressed, brain, neurons, cerebrospinal fluid | X | X | X | Endocytic pathway dysfunction | ||
CLN3
| Ubiquitously expressed, CNS, immune and circulatory systems, iPSC, neural progenitor cells, colorectal cancer cells | X | X | X | X | X | TGN is impaired, localized on the lysosome, cellular proliferation, apoptosis and synaptic transmission |
CLN4
| Ubiquitously expressed, neuronal synapses (1% of total synaptic vesicle-associated proteins) | X (Type A) | X | X | – | – | Type: B manifests movement abnormalities with dementia |
CLN5
| Ubiquitously expressed in human tissue, CNS, peripheral organs and tissues, neurons (ganglionic eminence) and microglia | X | X | X | Endosomal sorting, the stability of sortilin and CIMPR both declines, defective myelination | ||
CLN6
| Ubiquitously expressed | X | X | X | X | manifest characteristic cholesterol and subunit c of mitochondrial ATP synthase (SCMAS), aberrant biometal metabolism | |
CLN7
| Ubiquitously expressed at a very low level, its expression in the liver, heart, and pancreas (markedly higher) | X | X | X | X | loss of CLN7 causes depletion of soluble proteins in the lysosomes impairing reactivation of mTOR | |
CLN8
| Ubiquitously expressed, high level expression in cerebral cortex and hippocampus in electrical kindling model of epilepsy | X | X | X | X | progressive motor neuron dysfunction and retinal degeneration, lysosomal β-glucosidase deficiency, | |
CLN9
| Currently designated as CLN4 | – | – | – | – | – | |
CLN10
| Ubiquitously expressed, brain | X | X | X | X | CTSD-processing | |
CLN11
| Ubiquitously expressed, CNS, neuron, microglia, astrocytes, and endothelial cells | X | X | X | – | – | significantly activated microglia after TBI, the elevated lysosomal biogenesis in activated microglia, which increased cerebrocortical neuron damage, reduces lysosomal biogenesis |
CLN12
| Ubiquitously expressed, ventral midbrain, including substantia nigra (high lever), kidney and skeletal muscle (low level) | X | X | X | – | – | extrapyramidal involvement, oxidative-stress in neuroblastoma cells; dysregulated neurotransmission |
CLN13
| CTSF is expressed at a high level in cerebrocortical, hippocampal and cerebellar neurons | X | X | X | – | – | neurons showed accumulation of eosinophilic granules |
CLN14
| Ubiquitously expressed, cerebrocortical and cerebellar Purkinje cells, pyramidal cell layers of the hippocampus (high levels) | X | X | X | – | – | disrupt KCTD7-Cullin-3 interactions |
CLN1/PPT1
CLN2/TPP1
CLN3/ Batten disease
CLN4 / DNAJC5
CLN5
CLN6
CLN7
CLN8
CLN9/reclassified as CLN4
CLN10/ CTSD
CLN11/PGRN
CLN12/ATP13A2
CLN13/CTSF
CLN14
Emerging new roles of the lysosome in the context of NCLs
Current and emerging therapeutic strategies
NCL-related proteins | Natural History/ Treatment | National Clinical Trial Number | Study Location | Status | Phase |
---|---|---|---|---|---|
CLN1
| Single Group Assignment, Procedure: Surgery to implant human CNS stem cells, single dose Drug: Immunosuppression for 12 months post transplant | NCT00337636 | Oregon Health and Science University StemCells, Inc. | Completed | Phase 1 |
Single Group Assignment, Interventional, Small Molecule, Cystagon and N-acetylcysteine | NCT00028262 | NICHDd/NIH | Completed | Phase 4 | |
CLN2
| Single Group Assignment, Biological, ERT (BMN-190 [recombinant human tripeptidyl peptidase-a (rhTPP1/cerliponase alfa)]), 30-300 mg ICV infusion administered every other week for at least 48 weeks | NCT01907087 | NCHb University Hamburg-Eppendorf Guy’s St & Thomas NHS Foundation Trust Hospital for NHS Foundation Trust BioMarin Pharmaceutical | Completed | Phase 1/2 |
Parallel Assignment, Biological, AAVrh.10CUhCLN2 (either 9.0 × 10^11 or 2.85 × 10^11 genome copies) | NCT01414985 | WCMCc | Active, not recruiting | Phase 1&2 | |
Parallel Assignment, Genetic: AAVrh.10CUhCLN2 (either 9.0 × 10^11 or 2.85 × 10^11 genome copies) | NCT01161576 | WCMC | Active, not recruiting | Phase 1 | |
Parallel Assignment, Genetic: AAV2CUhCLN2 (3 × 10^12 particle units) | NCT00151216 | WCMC | Active, not recruiting | Phase 1 | |
Observational, Case-Only | NCT01035424 | WCMC | Active, not recruiting | N/A | |
Single Group Assignment, Biological: BMN-190, 300 mg ICV infusion administered every other week for up to 240 weeks Device: Intraventricular access device, surgical implantation of an MRI compatible ICV access device in the lateral ventricle of the right hemisphere | NCT02485899 | Columbus, Ohio, United States Hamburg, Germany Rome, Italy London, United Kingdom BioMarin Pharmaceutical | Active, not recruiting | Phase 1/2 | |
Single Group Assignment, Biological: BMN-190 & recombinant human tripeptidyl peptidase-1 (rhTPP1), an age-appropriate dose of BMN 190 administered via intracerebroventricular (ICV) infusion every other week (qow) for a duration of 144 weeks Device: Intraventricular access device, surgical implantation of an MRI compatible ICV access device in the lateral ventricle of the right hemisphere | NCT02678689 | Columbus, Ohio, United States Hamburg, Germany Rome, Italy London, United Kingdom BioMarin Pharmaceutical | Enrolling by invitation | Phase 2 | |
Observational, Natural History, Primary Outcome: correlation analysis between genotype (genetic constitution) and baseline [time frame: 18 months] | NCT00151268 | WCMC | Completed | N/A | |
Single Group Assignment, Procedure: Surgery to implant human CNS stem cells (HuCNS-SC) Drug: Medication to suppress the immune system for 12 months post transplant | NCT00337636 | Oregon Health and Science University StemCells, Inc. | Completed | Phase 1 | |
CLN3
| Crossover Assignment, Drug: Small Molecule (Mycophenolate mofetil) | NCT01399047 | University of Rochester | Completed | Phase 2 |
Natural History, Cohort | NCT03307304 | NICHD/ NIH | Recruiting | ||
CLN6
| Observational/Natural History, Primary Outcome: disease progression [time frame: 3 years] | NCT03285425 | NCH | Recruiting | N/A |
Single Group Assignment, Gene Therapy, Drug:scAVV9.CB.CLN6 administered by intrathecal injection | NCT02725580 | NCH | Recruiting | Phase 1/2 | |
General Batten Disease | Observational [Patient Registry], Cohort, Primary Outcome measures: Refinement and validation of UBDRS, The natural history of Batten Disease [both time frames:10 years] | NCT01873924 | University of Rochester | Recruiting | N/A |
Observational, Cross-Sectional Primary Outcome measure: sleep disturbance Secondary Outcome measure: epilepsy onset, Blindness [both time frames: 1 year] | NCT01966757 | NCH | Completed | N/A |