Autophagy in the Neuronal Ceroid Lipofuscinoses (Batten Disease)

Abstract

The neuronal ceroid lipofuscinoses (NCLs), also referred to as Batten disease, are a family of neurodegenerative diseases that affect all age groups and ethnicities around the globe. At least a dozen NCL subtypes have been identified that are each linked to a mutation in a distinct ceroid lipofuscinosis neuronal (CLN) gene. 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. The mechanisms regulating the accumulation of this material are not entirely known. The CLN genes encode cytosolic, lysosomal, and integral membrane proteins that are associated with a variety of cellular processes, and accumulated evidence suggests they participate in shared or convergent biological pathways. Research across a variety of non-mammalian and mammalian model systems clearly supports an effect of CLN gene mutations on autophagy, suggesting that autophagy plays an essential role in the development and progression of the NCLs. In this review, we summarize research linking the autophagy pathway to the NCLs to guide future work that further elucidates the contribution of altered autophagy to NCL pathology.

Keywords: Batten disease; autophagosome; autophagy; lysosome; mTOR; model system; neurodegeneration; neuronal ceroid lipofucinosis.

FIGURE 1

Overview of the autophagy pathway. The autophagy proteins are involved in the formation of autophagosomes via phagophore maturation including the ULK1 complex acting on the Class III PI3K complex I to generate PIP3. The autophagy proteins also process LC3 into LC3-I, which matures into LC3-II via attachment to PE on the phagophore. Through phagophore closure, an autophagosome is formed and further matured via autophagosome-lysosomal fusion through the Class III PI3K complex II. Figure concept was adapted from Bento CF. et al. (2016). Akt/PKB, protein kinase B; ATG3, ubiquitin-like-conjugating enzyme ATG3; ATG4, cysteine protease ATG4; ATG5, autophagy protein 5; ATG7, ubiquitin-like modifier-activating enzyme ATG7; ATG9, autophagy protein 9; ATG10, ubiquitin-like-conjugating enzyme ATG10; ATG12, ubiquitin-like protein ATG12; ATG13, autophagy-related protein 13; ATG14, BECN1-associated autophagy-related key regulator; ATG16-1, autophagy-related protein 16-1; ATG101, autophagy-related protein 101; BECN1, beclin-1; FIP200, focal adhesion kinase family interacting protein of 200 kDa; LC3/ATG8, microtubule-associated protein 1A/1B-light chain 3/autophagy-related gene 8; PE, phosphatidylethanolamine; PIP3, phosphatidylinositol-3,4,5-triphosphate; VPS15, vacuolar protein sorting 15; VPS34, vacuolar protein sorting 34; ULK1, UNC51-like autophagy activating kinase 1; UVRAG, UV radiation resistance-associated gene; WIPI2, WD repeat domain phosphoinositide-interacting protein 2.

FIGURE 2

The involvement of CLN proteins in endocytosis, exocytosis, ER-Golgi protein trafficking, autophagosome formation, and lysosome formation. The ULK1 complex (proteins above the yellow background), the Class III PI3K complex I (proteins above the red background), and the autophagy proteins (blue) are required for the formation and maturation of autophagosomes. Some of the CLN proteins (green) affect mTORC1, a protein complex that regulates autophagosome formation and lysosomal biogenesis via TFEB. The black arrows indicate the autophagy pathway and red arrows indicate supporting evidence of an effect of a CLN protein on a given autophagic process. Protein overlaps are representative of protein-protein interactions. * indicates the observation was made only for the D. melanogaster homolog and ** indicates the observation was made only for the D. discoideum homolog. Note that the positions of the CLN proteins depicted in the figure are not necessarily representative of their actual localization in the cell. Please refer to Table 1 for information on the localizations of the different CLN proteins. Akt, protein kinase B; AMPKα, AMP-activated protein kinase α1/2; ATG3, ubiquitin-like-conjugating enzyme ATG3; ATG4, cysteine protease ATG4; ATG5, autophagy protein 5; ATG7, ubiquitin-like modifier-activating enzyme ATG7; ATG9, autophagy protein 9; ATG12, ubiquitin-like protein ATG12; ATG13, autophagy-related protein 13; ATG14L, BECN1-associated autophagy-related key regulator-like; ATG16-1, autophagy-related protein 16-1; ATG101, autophagy-related protein 101; BECN1, beclin-1; CAMKI, calmodulin-dependent protein kinase I; CLN5, ceroid lipofuscinosis neuronal 5; CLN6, ceroid lipofuscinosis neuronal 6; CLN8, ceroid lipofuscinosis neuronal 8; COPII, coat protein complex II; CTSD, cathepsin D; DNAJC5, DnaJ heat shock protein family Hsp40 member C5; Dynamin-1, dynamin-1; ER, endoplasmic reticulum; ERK1/2, extracellular signal-regulated protein kinase 1/2; FIP200, focal adhesion kinase family interacting protein of 200 kDa; GRN, progranulin; HMGB1, high mobility group box 1; LC3/ATG8; microtubule-associated protein 1A/1B-light chain 3/autophagy-related gene 8; LC3-I, processed LC3; LC3-II, lipid-attached membrane-bound LC3; MAPK14, mitogen-activated protein kinase 14; MFSD8, major facilitator superfamily domain containing 8; mTORC1, mammalian target of rapamycin complex 1; P, phosphate; p62, p62/sequestosome 1; p70S6K, p70 S6 kinase; PE, phosphatidylethanolamine; Protein, protein cargo; PPT1, palmitoyl protein thioesterase 1; RHEB, ras homolog enriched in the brain; SNAP23, synaptosomal-associated protein 23; SNAP25, synaptosomal-associated protein 25; TFEB, transcription factor EB; TPP1, tripeptidyl peptidase 1; Ub, ubiquitin; VPS15, vacuolar protein sorting 15; VPS34, vacuolar protein sorting 34. ULK1, UNC51-like autophagy activating kinase 1; WIPI2, WD repeat domain phosphoinositide-interacting protein 2.

FIGURE 3

The involvement of CLN proteins in autolysosome formation, cargo degradation, autophagic lysosome reformation, and mitophagy. The CLN proteins (green) modulate various proteins (magenta, yellow, orange) that impact the indicated processes within lysosomes, such as intraluminal acidification and enzymatic degradation, and the fusion of lysosomes with autophagosomes (denoted as autolysosomes) or with mitochondria (known as mitophagosomes, not represented here). While DNAJC5 is involved in regulating endolysosomal trafficking and the fusion between endosomes and autolysosomes, MFSD8 is involved in ALR. The black arrows indicate the autophagic processes starting from autolysosome/mitophagosome formation to ALR. Red arrows indicate supporting evidence of the involvement of a CLN protein within the latter processes of autophagy. Protein overlaps are representative of protein-protein interactions. * indicates the observation was made only for the D. melanogaster homolog and ** indicates the observation was made only for the D. discoideum homolog. Note that the positions of the CLN proteins depicted in the figure are not necessarily representative of their actual localization in the cell. Please refer to Table 1 for information on the localizations of the different CLN proteins. ATP13A2, polyamine transporting ATPase 13A2; BNIP3, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3; BNIP3L, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like; CLN3, ceroid lipofuscinosis neuronal 3; CLN5, ceroid lipofuscinosis neuronal 5; CLN6, ceroid lipofuscinosis neuronal 6; CLN8, ceroid lipofuscinosis neuronal 8; Cortactin, cortactin; CTS, cathepsin B/D/Z; CTSD, cathepsin D; CTSF, cathepsin F; DNAJC5, DnaJ heat shock protein family Hsp40 member C5; ESCRT complex, endosomal sorting complex required for transport complex; GALNS, N-acetylgalactosamine-sulfate; GATE16, GABA type A receptor-associated protein-like 2; GM2A, GM2 ganglioside activator; GRN, progranulin; HDAC6, histone deacetylase 6; LAMP1, lysosomal-associated membrane 1; LAMP2, lysosomal-associated membrane 2; LC3-II, lipid-attached membrane-bound LC3; Lysosomal proteins, PPT1/TPP1/β-glucuronidase/β-hexosaminidase/Saposin C/D; MFSD8, major facilitator superfamily domain containing 8; p62, p62/sequestosome 1; PE, phosphatidylethanolamine; Protein, protein cargo; PEMT2, phosphatidylethanolamine N-methyltransferase 2; PPT1, palmitoyl protein thioesterase 1; RAB2, ras-related protein Rab-2A; RAB7, ras-related protein Rab-7A; RILP, RAB-7A-interacting lysosomal protein; SNAP23, synaptosomal-associated protein 23; Ub, ubiquitin; V-ATPase, vacuolar-type ATPase; VAPA; vesicle-associated membrane protein A; VPS4; vacuolar protein sorting 4.