Table 1 -.
Summary of genes associated with FTD and ALS and their role in lysosome function
| Gene | Protein | Genome location | Role(s) in lysosome function | Type of mutation | Clinical Pheno-types(s) | Mutation Frequency | Effect of genetic mutation/variant | References |
|---|---|---|---|---|---|---|---|---|
| C9orf72 | C9orf72 | 9p21.2 | GTPase-activating protein (GAP) complex with SMCR9-WD41; lysosome trafficking; mTORC1 signaling | G4C2-repeat expansion | FTD, ALS | Common; Varies by population; ~42.1%* | Loss of C9orf72 function; gain of DPR and RNA toxicity | (DeJesus-Hernandez et al., 2011; Le Ber et al., 2009; Shao et al., 2020; Su et al., 2020; Tang et al., 2020) |
| GRN | Progranulin | 17q21.31 | Lysosome homeostasis; Hydrolase trafficking and function | Haplo-insufficiency; nonsense | FTD, NCL (CLN11) | Common; Varies by population; ~34.6%* | Loss of function; Lysosome impairment | (Arai et al., 2006; Baker et al., 2006; Holler et al., 2017; Neumann et al., 2006) |
| MAPT | Tau | 17 | Trafficking of autophagic vesicles and autolysosome fusion | Missense/deletion Intronic | FTD | Common; Varies by population; ~23.2%* | Tau hyperphosphorylation and protein aggregation | (Hutton et al., 1998; Lim et al., 2001; Pacheco et al., 2009) |
| TARDBP | TDP-43 | 1p36 | Lysosomal fusion and regulation of lysosomal protein expression | Mainly missense Truncating | FTD, ALS | ~3% | TDP-43 hyperubiquitination and aggregate formation | (Arai et al., 2006; Gao et al., 2018; Neumann et al., 2006)[14, 15, 216] |
| TMEM 106B | Transmembrane protein 106B | 7p21.3 | Lysosomal membrane protein, lysosome trafficking | Polymorphism; Missense (HLD) | FTD, HLD | Risk factor; Rare (HLD) | Increased TMEM106B levels?; impaired Lysosome: Loss of function (HLD) | (Brady et al., 2013; Nicholson et al., 2013; Simons et al., 2017; Van Deerlin et al., 2010) |
| CHMP2B | Charged multivesicular body protein 2B | 3p11.2 | Endocytic multivesicular body formation | C-terminal truncation | FTD | Rare | Loss of function | (Lindquist et al., 2008; Skibinski et al., 2005) |
| TBK1 | TANK Binding Kinase 1 | 12q14.2 | autophagy; lysophagy; phosphorylates OPTN | Missense; truncation | FTD, ALS | ~1.0% ALS; ~1.8% FTD | Loss of function | (Abramzon et al., 2020; Cirulli et al., 2015; Freischmidt et al., 2015) |
| OPTN | Optineurin | 10p13 | Autophagy receptor; Clearance protein aggregates; damaged organelles | Missense | FTD, ALS | Rare | Loss of function | (Bussi et al., 2018; Maruyama et al., 2010; Moore and Holzbaur, 2016; Pottier et al., 2015) |
| VCP | Valosin containing protein | 9p13.3 | Lysophagy; Sorting of proteins/aggregates to lysosomes | Missense | FTD, ALS MSP | Rare | Loss of function | (Johnson et al., 2010) |
| MFSD8 | Major facilitator superfamily domain containing 8 | 4q28.2 | Likely transports solutes across lysosome membrane; substrate unknown | Missense | FTD, NCL (CLN7) | Rare | Loss of function | (Geier et al., 2019) |
| CTSF | Cathepsin F | 11q13 | Lysosomal cysteine protease; multiple substrates | Missense | FTD, NCL (CLN13) | Rare | Loss of function | (van der Zee et al., 2016) |
| SQSTM1/p62 | Sequestosome-1/p62 | 5q35.3 | Facilitating protein aggregate degradation in lysosome; Autophagosome; mTORC1 regulation | Missense; nonsense | FTD, ALS | ~3% | Loss of function | (Hardy and Rogaeva, 2014; Le Ber et al., 2013) |
*
Population described in (Moore et al., 2020)