Table 2.

Comparison of invertebrate genetic models of ALS: Drosophila melanogaster.

Groups	Type	Characterization	Phenotype	Influence	Reference
Drosophila melanogaster genetic models	SOD1	Produced by• hSOD1WT • SOD1mutations (A4V/G37R/G85R/H48R/H71Y)	hSOD1 mutations (G85R/H48R/H71Y) in endogenous dSOD1 (1) Leads to reduced survival, developmental defects, and dyskinesia Only hSOD1WT in motor neurons(1) Prolong lifespan: without affecting locomotion or motor neuron survival(2) Does not prevent age-related movement disordershSOD1WT and hSOD1 mutations (A4V/G85R)(1) Electrophysiological defects(2) The SOD1 abnormal accumulation (3) The stress response surrounding glial cells(4) Cellular (motor neurons) and non-cellular (glial cells) autonomic damage• Manifested as: the SOD1 toxicity propagate from one cell to another, induces progressive motor dysfunctions	(1) Antioxidant compounds: • Improve exercise performance • Prolong lifespan • Reduce SOD1 cytoplasmic inclusion bodies	(Parkes et al., 1998; Clement et al., 2003; Boillée et al., 2006; Watson et al., 2008; Walters et al., 2019; Braems et al., 2021; Layalle et al., 2021; Liguori et al., 2021)
	TDP-43	Produced by • Endogenous dTDP • hTDP-43WT • TDP-43 mutations (A315GOF)	Endogenous dTDP (1) Lack of dTDP: • Appears externally normal • But presents the deficiency of locomotion behaviors, the reduction of life span, the anatomical defects of NMJs, and the decrease of dendrite branches (2) Overexpression of dTDP: • Premature lethality • Neuronal loss • The defects of NMJs • Locomotor deficitshTDP-43WT, hTDP-43 mutations and TBPH (1) Overexpression of hTDP-43WT and TBPH: • affects lifespan, mobility, axonal transport, and pupal shell sealing (2) Depletion of TBPH: • Leads to movement disorders and shortened lifespan (3) Overexpression of hTDP-43: • Induces mitochondrial dysfunction • Inhibits mitochondrial complex I activity • Highly fragmented mitochondria in the axons of motor neuronsMetabolic dysfunction (1) Glucose metabolism: • Increased Pyruvic acid • Increased the mRNA level of PFK(2) Lipid metabolism: • Reduced carnitine shuttle and β oxidation	(1) Gene modification of TDP-43: • Upregulation of Pab1-binding protein 1: enhances the TDP-43 toxicity and result in more severe TDP-43 induced phenotypes • Overexpression of ubiquilin 1: enhances the severity of TDP-43 phenotypes • Co-expression of VCP: induced TDP-43 phenotypes (2) The PTK2-TBK1-SQSTM1 axis: • PTK2 inhibition: significantly reduced the ubiquitin aggregate and reduced the cytotoxicity in the TARDBP-induced protein disease • The non-phosphorylated form of SQSTM1: significantly inhibited the accumulation and neurotoxicity of insoluble polyubiquitin proteins (3) NBs, Mp, CG5445 and NEAT1-1: • alleviated the cytotoxicity of TDP-43 Drosophila neurons and improved motor or eye symptoms (4) Gemin3: • Aggravates vitality defects, motor dysfunction, and muscle atrophy while inhibiting the overgrowth of the NMJ (5) Knocking down the 3-fold lethal [Su (Tpl)] gene inhibitor: • Inhibits the morphological defects of compound eye and medial retina	(Feiguin et al., 2009; Kim et al., 2009; Lu et al., 2009; Elden et al., 2010; Hanson et al., 2010; Li et al., 2010; Ritson et al., 2010; Voigt et al., 2010; Estes et al., 2011; Lin et al., 2011; Miguel et al., 2011; Maccioni et al., 2018; Uechi et al., 2018, p. 3; Zhang et al., 2018a; Cacciottolo et al., 2019; Manzo et al., 2019; Walters et al., 2019; Lee et al., 2020; Wang et al., 2020; Layalle et al., 2021; Liguori et al., 2021; Matsukawa et al., 2021)
	FUS/TLS	Produced by • hFUS/TLS drosophila orthodox • hFUS/TLSWT • FUS/TLS mutations (R518K/R521C/R521H)	hFUS/TLS mutations (R518K/R521C/R521H)(1) Severe neurodegeneration in Drosophila eyes(2) Locomotor dysfunction and premature lethality (3) Synaptic damage • Manifested as: progressive age-dependent neuronal degeneration hFUS/TLS drosophila orthodox (Cabeza) deficient (1) Reduced lifespan and the locomotor deficits hFUS/TLSWT (1) Only resulted in very mild eye degeneration	(1) Associate with TDP-43: • Both FUS/TLS and TDP-43 proteins exert some damaged effect together in vivo in the pathogenesis of ALS (2) Cabeza: • Functional loss are fatal: only a few develop into adulthood, with severely shortened lifespan and motor disorders • Expressing Caz: can repair climbing and flight defects • Overexpressing Caz/FUSWT exhibit opposite NMJ electrophysiological phenotypes (3) Inhibiting nuclear output of FUS: • Chameau and NAA60: inhibit the rough eye phenotype induced by caz knockdown • XPO1 and NUP 154: down-regulation prevents the toxicity induced by FUS (4) Kap-β2: • Inhibits PY-NLS and reverses FUS fibrosis • Rescues degeneration caused by FUS-ALS	(Chen et al., 2011; Lanson et al., 2011; Guo et al., 2018; Braems et al., 2021; Yamaguchi et al., 2021)