Fly Neurogeneration Genes Table

Adult Drosophila CNS Degeneration Caused By Loss-of-Function Mutations

 Drosophila genes in which mutations cause progressive, adult-onset histological defects in the fly brain (exceptions explained in note a). mouse gene and human gene columns show orthologs of the respective fly genes, called by Flybase/InParanoid or NCBI/Homologene. Mammalian genes are in red if they are also associated with neurodegeneration. Mutations are recessive loss-of-function alleles unless otherwise noted.Links within the table are to the following sites: fly gene > Flybase; mouse gene > Mouse Genomics Informatics; human gene > Entrez Gene; human disease > OMIM.

The allele column shows mutations of the respective fly genes that cause neurodegeneration. Key: Allele name(s): mutagen, allele strength. Mutagens: EMS= ethyl methanesulfonate; P= P element transposon insertion; PE= imprecise P element excision; PBac=piggyBac transposon insertion. Allele strength: amorph=complete loss of function determined genetically; null=no detectable protein or mRNA; hypomorph: partial loss of function.

The [FA] citation in the expression in adult fly column indicates data summarized from FlyAtlas [1]  (individual genes do not have unique URLs). FlyAtlas is a microarray database of gene expression in the following adult organs: brain, head, thoracic ganglion, salivary gland, crop, midgut, tubule, hindgut, ovary, testis, male accessory glands, spermatheca. Enrichment in an organ is relative to expression in the entire adult fly.

This table is based on Table 1 and Box 1 from Nature Reviews Genetics, vol. 10 no. 6, 2009, DOI: 10.1038/nrg2563  Nature Publishing Group, a division of Macmillan Publishers Limited.




lm38, lm15, lm115: EMS, lethal hypomorphs [3]. j40/j19,j40/j50: EMS, temperature-sensitive heteroallelic combos [3]. acetyl-cholinesterase Strong in brain neuropil, except weaker in lamina [4]. Enriched in brain, thoracic ganglion, gut [FA] Ache:

delayed postnatal development, organophosphate sensitivity, death by 3 weeks.

ACHE Fly: Large mutant brain clones induced in embryogenesis show degeneration [2]. Paralysis and quick death at 32∞; abnormal neuropil after 11d at 29∞[3].
Adar 1F11F4: PE, likely amorph RNA-specific adenosine deaminase enriched in brain [FA] Adarb1:

seizures, death by 20d.

ADARB1 Fly: Multiple behavioral phenotypes. ADAR is the sole pre-mRNA editing enzyme in flies; most known target mRNAs encode ion channels [5].



EMS, hypomorph

AMP-activated protein kinase

beta subunit

Not detected [FA]. cDNAisolated from adult head. Ubiquitous in embryo [6]. Prkab1 PRKAB1 Fly: Null allele is lethal. Retinal and optic lobe degeneration in 1-day old flies observed with loss of function limited to eye and select brain regions. Climbing defect gets worse with age. Pupal brains normal [6].
Apc Q8: EMS, temperature-sensitive. Binds beta-catenin & microtubules Widespread & enriched in brain [FA] Apc:

Heterozygotes: intestinal polyps & colorectal cancer; homozygotes are embryonic lethal


adenomatous polyposis of the colon

Fly: Retinal degeneration onlya in newly-eclosed adults. Normal eye development. Apoptotic death of photo-receptors, suppressed by loss of arm (beta-catenin) [7].

Mouse & Human:tumor suppressor gene, loss of function alleles act dominantly.


(Autophagy-specific gene7)

d77/d14b: PE, amorph E1 Ub-activation-like enzyme widespread; enriched in tubule [FA] Atg7:

neurodegeneration, behavioral defects, death by 25 weeks[8].

ATG7 Fly: Hypersensitive to paraquat. Climbing defect at 30d [9].

Mouse: Conditional CNS-targeted knockout.



1: P, null dynamin-like GTPase strong & widespread [FA] Atl1 ATL1:

spastic paraplegia 3

Fly: Sterile, small adults. Dopaminergic neuron loss. Climbing defect fully rescued by pan-neuronal expression of wild type atl, partially rescued by expression in dopaminergic but not cholinergic neurons [10].

Human disease due to dominant mutations; expression of Atl with these mutations in the fly causes climbing defects & dopaminergic neuron loss [10].

ATP6 1: spontaneousc F1F0-ATP synthase subunit widespreadd mt-Atp6 MTATP6:

Leigh syndrome

Fly: Subtle thoracic ganglia defects; no gross histological defects in aged brains. Enhances sesBphenotype. Thoracic muscle degeneration. Mechanical stress sensitivity. Abnormal mitochondrial ultrastructure [11].
ATPalpha 2206: P, hypomorph Na+/K+ ATPase alpha subunit widespread; enriched in brain and thoracic ganglion [FA] Atp1a3:

neonatal lethal. Heterozygous mice: learning defects, hyperactivity.


dystonia 12

Fly: Degeneration with both recessive and dominant alleles [12].

Mouse: beta subunit gene Atp1b2 knockout causes neurodegeneration and death at 17-18d [13].

Human diseases caused by dominant allele.


(blue cheese)

3/Df(2L)clot7: P/deletion, hypomorph/null BEACH, WD40, FYVE domains widespread; enriched in brain and tubule [FA]. In situ signal in CNS cell bodies but not in adjacent muscle or fat cells [14]. Wdfy3 WDFY3 Fly: holes mostly in retina; general loss of brain volume. Ub+inclusions. Increased apoptosis[14].

Human protein, a.k.a. Alfy, interacts with phosphatidylinositol-3-phosphate and may target protein aggregates for autophagic degradation[15].



1: P, strong hypomorph fatty acid CoA synthetase widespread but relatively low in brain [FA] Acsbg1 ACSBG2 Fly: Histological defects in optic lobe only [16].

Human:Adrenoleukodystrophy is caused by a recessive X-linked ABCD1 allele, affecting a peroxisomal transporter involved in importation or anchoring of the synthetase.


(cathespin D)

1: PE, null lysosomal protease strong & widespread [FA] Ctsd:

neurodegeneration, aberrant autophagy, death by 26d[17].


neuronal ceroid lipofuscinosis 10

Fly: Neuronal autofluorescence accumulation and inclusions; increase in apoptosis after 30d [18].

Mouse: degeneration persists in Bax knockout background (Bax is a pro-apoptotic gene).

Cha ts2/Df(3R)Cha: EMS/deletion, temperature-sensitive /null choline acetyl-transferase Optic & antennal lobes, central brain neuropils [4]. Strong expression limited to brain & thoracic ganglion [FA] Chat:

perinatal lethality, abnormal neuromuscular junction.


congenital myasthenic syndrome

Fly: Temperature sensitive allele: adult histological defects after normal brain structure allowed to develop [4].

(Cystein string protein)

X1: P, near-null Hsp40-like; component of synaptic vesicles strong & widespread [FA] Dnajc5b DNAJC5B


Fly: Subtle synaptic degeneration seen at TEM level [19].

Mouse: Knockout of paralog Dnajc5 dies within 3 months, with progressive neuromuscular junction degeneration and behavioral abnormalities[20].

dare 4/34: PE/PE, hypomorph/


ferredoxin reductase widespread [FA] Fdxr FDXR Fly: Null alleles are larval lethal. Significant pupal lethality; severe uncoordination in eclosed adults [21].
DJ-1alpha &


alphadelta72: PE, null [22]; pan-neuronal or dopaminergic RNAi [23].

betadelta93: PE, null [22]

unknown function or activity

alpha:principally in testes [22]; high in testes, low in brain & thoracic ganglion, not in other tissues [FA].

beta:widespread[22] [FA].





Parkinson disease 7

Fly: Two paralogs compared to single mammalian gene. Double mutant has increased sensitivity to oxidative stress [22]. Dopaminergic cell loss; ubiquitous DJ-1alpha RNAi is lethal [23], in contrast to viability for null allele reported in [22].


1: EMS


Low in brain, enriched in crop & hindgut [FA]e. no significantly

similar gene

no significantly

similar gene

Fly: Abnormal glial morphology in young adults [24].
Eaat1 RNAi in Eaat1-expressing cells except in lamina glutamate transporter glial processes in CNS [25]. High in brain & thoracic ganglion, moderate in gut, low elsewhere [FA]. Slc1a3:

ataxia, abnormal Purkinje cell innervation by climbing fibers[26].

SLC1A3 Fly: Behavioral defects. Increased sensitivity to paraquat. Phenotypes rescued by expression of human paralogSLC1A2 [25].

Mouse: Knockout of neuronally-expressed paralog Slc1a1 causes neurodegeneration [27].

Human: lowered SLC1A2 activity is associated with many cases of sporadicamyotrophic lateral sclerois.


(easily shocked)

1: EMS; likely null ethanolamine kinase widespread [FA] Etnk1 ETNK1 Fly: Mechanical shock causes brief hyperactivity and then paralysis; possible epilepsy model. Electrophysiological defects in giant fiber pathway [28,29].


rev: P, hypomorphf actin-binding broadly in brain[30]; widespread, enriched in brain, thoracic ganglion, ovary [FA] Enah:

Viable with CNS developmental defects

ENAH Fly: Null alleles are embryonic lethal. Adult, brain-specific loss of function results in apoptotic degeneration principally in optic lobe[30].


1: P, hypomorph pantothenate kinase widespread [FA] Pank1 PANK1 Fly: Flight and climbing defects. Paraquat sensitivity [31].

Mouse paralog Pank2knockout causes retinal degeneration.

Human: Mutation of paralog PANK2 causespantothenate kinase-associated neurodegeneration(a.k.a. Hallervorden-Spatz syndrome).

futsch olk1: EMS, hypomorph microtubule-associated protein 1B embryonic CNS [32]. MAP1s in general are expressed  in developing and mature neurons [33]. Mtap1b:

CNS developmental defects

MAP1B Fly: Null allele is lethal. Learning defect observed before brain histological defects. Partial rescue by Tau[34].

Human: Dominant splicing mutation in the paralog MAPT (Tau) causes frontotemporal dementia.



PC64: EMS, hypomorph citrate synthase strong & widespread [FA] Cs CS Fly: Mechanical shock causes brief hyperactivity and then paralysis; possible epilepsy model. Electrophysiological defects in giant fiber pathway [28,35].
levy 1: EMS, null subunit VIa cytochrome C oxidase (COX, complex IV of electron transport chain) strong & widespread [FA] Cox6a1 COX6A1 Fly: Histological defects limited to retina & optic lobes [36].

Human: Leigh syndromes (here andhere) can be caused by mutation of LRPPRC or COX10.


a.k.a. CG5483

e03680: PBac, hypomorphg protein kinase,


widespread; enriched in brain & thoracic ganglion [FA] Lrrk2 LRRK2:

Parkinson disease 8

Fly: Conflicting data as to dopaminergic neuron lossg [37,38].

Human disease due to dominant mutations.

MAGE RNAi:hypomorph unknown function or activity widespread, enriched in flight muscle & ovary; most or all brain neurons, low in glia [39]. widespread; enriched in ovary [FA]. Ndnl2 NDNL2 Fly: Loss of function via RNAi in embryos is lethal; in larval brain causes neuroblast overproliferation; and in adult causes retinal apoptosis or brain degeneration, depending on location of RNAi [40].
Nmnat 2: EMS, strong hypomorph or null. nicotinamide mononucleotide adenylytransferase cell bodies of optic lobes and brain [41] Nmnat1 NMNAT1 Fly: Retinal degeneration onlya and ERG defects. Normal photoreceptor development [41]. Lethal allele studied in eye by mosaic analysis.

Mouse slowed axonal Wallerian degeneration (Wlds) caused by overexpression of fusion of Ube4b fragment to Nmnat1 [42].


(Niemann-Pick Type C)

1: PE, null. lysosomal membrane protein binds & may transport cholesterol widespread [FA] Npc1:

Purkinje cell degeneration, abnormal cholesterol metabolism.


Niemann-Pick disease, type C

Fly: Adult phenotypes examined by feeding cholesterol to null mutant larvae. Shortened lifespan of these adults rescued by neuronal expression of normal npc1a; partial rescue by glial expression. Increased cholesterol, appearance of multivesicular bodies[43].

Mouse: Double Npc1 Npc2 mutant indistinguishable from single Npc1 mutant [44].

npc2a &

 npc2b, a.k.a. CG3153

2a239376, or 271: PE, null

2b1819, or 22: PE, null

lysosomal sterol-binding proteins 2a:widespread, enriched in brain, thoracic ganglion, salivary gland [FA]

2b: widespread, enriched in gut [FA]


tremor, ataxia at 55d; death at ~120d; Purkinje cell degeneration, abnormal lipid storage[44].


Nieman-Pick disease, type C2

Flies have 8 npc2genes. Null 2a mutants are viable & fertile with abnormal sterol accumulations and vesicular structures but grossly normal CNS. 2a; 2b double mutant escapers have increased apoptotic neuronal death [45].

Mouse: Purkinje cell loss delayed compared to Npc1 knockout [44].

parg 27.1: PE, null poly(ADP-ribose)


widespread, enriched in ovary [FA] Parg:

embryonic lethal

PARG Fly: Mobility defects. Nuclear aggregates of unknown composition[46]. Poly(ADP-ribosyl)ation is a reversible protein modification that can regulate DNA repair and other processes [47].

Mouse: Partial loss of function allele is viable but susceptible to radiation, alkylating agents, induced diabetes.



13, 25, 45: PE, null E3 ubiquitin ligase widespread, enriched in testes [FA] Park2:

behavioral defects, dopaminergic neuron loss in some but not all knockout alleles


Parkinson disease 2

Fly: Principal pathology is in mitochondria of sperm & flight muscles. Dopaminergic neurons are smaller in size[48,49].

(PTEN-induced kinase 1)

D3, B9: PE, hypomorph [50]

ubiquitous RNAi[51]

5, 9: PE, likely null [52]


mitochondrial protein kinase widespread[50][FA] Pink1: normal number of dopaminergic neurons; mitochondrial defects PINK1:

Parkinson disease 6

Fly: Conflicting data on dopaminergic neuron loss. Male sterility and wing, muscle, and mitochondrial defects[50,51,52].

a.k.a. CG5629

1/33: P/PE, hypomorph/


phospho-pantothenoyl-cysteine synthetase widespread; enriched in brain [FA] Ppcs PPCS Fly: Hypomorphic alleles. Flight and climbing defects. Sensitive to paraquat. Near complete loss of head fat body [31].

(reverse polarity)

1:  P, hypomorph homeodomain

transcription factor

glia only in embryo and in adult visual system [53]. Enriched in brain & thoracic ganglion, very low elsewhere [FA] Alx4:

developmental skeletal defects.


parietal foramina 2

Fly: Hypomorphic allele. Apoptotic loss of both neurons and glia limited to optic lobe [54].


pdelta1: PE, strong hypomorph

mitochondrial membrane protease

widespread, enriched in brain, thoracic ganglion, ovary, testes [FA] Parl:

Early death. Normal mitochondrial structure at birth but cells undergo unregulated apoptosis [55].

PARL Fly: Retinal degeneration onlya and ERG defects; largely lethal allele studied in eye by mosaic analysis. RNAi in cells causes mitochondrial fragmentation. Very similar phenotypes to mitochondrial fusion gene opa1 [56].

Mouse: Parl may process Opa1 into [55]. Expression of Parl or Opa1 in cells causes mitochondrial aggregation[56].

Human: dominant mutations in OPA1 cause optic atrophy 1.


a.k.a. SdhA

1110: EMS, strong hypomorph

succinate dehydrogenase (complex II of electron transport chain)

strong & widespread [FA] Sdha SDHA:

mitochondrial complex II deficiency and Leigh syndrome

Fly: Retinal degeneration onlya, abnormal mitochondria structure & density. Lethal allele studied in eye by mosaic analysis [57].

(stress sensitive B)

1: EMS, strong hypomorph[11] mitochondrial ADP/ATP translocator strong & widespread [FA] Slc25a4:

myopathy and abnormal metabolism.

SLC25A4:progressive external opthalmoplegia 2 Fly: Thoracic muscles also degenerate. Mechanical stress sensitivity [11,28].

Human gene a.k.a. adenine nucleotide translocator (ANT1); disease caused by dominant alleles.

SNF4Agammaa.k.a. lochrig

loe: P, hypomorph

AMP-activated protein kinase gamma subunit

widespread, enriched in gut [FA] Prkag2 PRKAG2:

Wolff-Parkinson-White syndrome

Fly: Mutation affects 1 of 3 isoforms [58,59].

Human disease caused by a dominant allele.



1: P, strong hypomorph carbonyl reductase wdespread [FA] (see note h) (see note h) Fly: Apoptotic loss of neurons; increased susceptibility to oxidative stress. Rescued by neuronal but not glial expression. Overexpression protects from hyperoxia [60].
Sod n108: EMS, missense with no enzymatic activity Cu/Zn superoxide dismutase strong & widespread [FA] Sod1:

Increased loss of motor neurons after axonal injury


amyotrophic lateral sclerosis

Fly: Retinal degeneration onlya [61]

Human disease due to dominant mutations.



RNAi directed to neurons only: hypomorph microtubule-binding


widespread [FA]. Enriched at neuromuscular junction synapse [62]. Spast:

axonal swellings, more numerous with age; mild gait defects appear late


spastic paraplegia 4

Fly: Increased apoptosis, climbing defect, rescue with tubulin-binding drug vinblastine [63]. Null allele: rare adult escapers have neuromuscular junction & behavioral defects[64].

Human disease due to dominant loss-of-function mutations.



a.k.a. bench-warmer)

11F5E14.1N: EMS, likely null[65,66].

P1: P, hypomorph [67]

transporter glial cells [67]. Glial enrichment, also in neurons[65]. Neurons & muscle during development[68]. Widespread [FA]. Spns1:

lethality before weaning.

SPNS1 Fly: Semilethal, degeneration in survivors; progressive degeneration in eye clones [65]. Subtle degeneration & behavioral defects with hypomorphic allele [67]. Developmental synaptic abnormalities suppressed by loss of TGFb signaling; Spin localized to late endosomal/lysosomal membranes; rescue by neuronal or muscle expression [68].
swiss cheese (sws) 1: EMS, likely null[69,70]. membrane phospholipase; protein kinase A regulatory subunit neurons but not glia in brain[70]. Widespread, enriched in brain & thoracic ganglion [FA]. Pnpla6:

Hippocampus, thalamus, & cerebellar degeneration [71].


(a.k.a NTE):

spastic paraplegia-39

Fly: Increased apoptosis. Both neuronal and glial death[70,72].

Mouse:neurodegeneration due to conditional brain-specific knockout


a.k.a. ATM

RNAi with various drivers; hypomorphic ser/thr protein kinase Widespread, enriched in salivary & male accessory glands [FA]. Atm:

Locomotor and motor learning defects



Fly: Retinal degeneration onlya via apoptosis. Cell cycle re-entry precedes photoreceptor cell death. Suppressed by partial loss of cell cycle activator string [73].

(technical knockout)

25t: N-methyl-N’-nitro-N-nitrosoguanidine, hypomorph [74]. mitochondrial ribosomal constituent widespread [FA] Mrps12 MRPS12 Fly: Hearing and courtship defects. Developmental delay. Electrophysiological defects in giant fiber pathway [28,35,75].
torp4A RNAi with ubiquitous driver, apparent null. chaperone-like glycoprotein in ER brain, ovary, testes [76];

widespread [FA].


Heterozygotes are hyperactive with coordination defects. Homozygotes are perinatal lethal.


torsion dystonia 1

Fly: Retinal degeneration onlya [76]

Human disease caused by dominant mutations

Tpi sgk1: EMS?, hypomorph [77].

wstd1: EMS, hypomorph [78].

triose-phosphate isomerase strong & widespread [FA] Tpi1:

embryonic lethal.

TPI1:triosephosphate isomerase deficiency Fly: Temperature-sensitive alleles. Paralysis, seizures. Glycolytic enzyme, but no global energetic or metabolic impairment[77,78].

a.k.a. CG8743

1: PE, null lysosomal channel (see note i) Mcoln3:

behavioral defects, deafness (dominant)

MCOLN3 Fly: Partially lethal. Climbing and autophagy defects. Localized to lysosomal membrane. Increase of non-degraded lysosomal protein and lipid [79].

Mouse paralog Mcoln1knockout results in death at 8 months with retinal degeneration.

Human: loss of paralog MCOLN1 causes mucolipidosis IV.


(vacuolar peduncle)

1: EMS, null ras GTPase activating protein broad expression in brain, not in glia [80]. Widespread; enriched in brain, thoracic ganglion, ovary, male accessory glands [FA] Rasa1:

perinatal lethality, developmental defects.


basal cell carcinoma

Fly: Central brain and optic lobe defects, but retina is not affected; non-apoptotic cell death. Interactions with receptor tyrosine kinase-pathway genes, e.g., loss of EGF receptor activity at eclosion suppresses degeneration [69,80].



KE2.1: PE, null protein kinase-like abundant in head [81]. widespread; enriched in salivary & male accessory glands [FA]. Scyl1

Purkinje cell loss, optic nerve atrophy[82].

SCYL1 Fly: Developmental eye defect; retinal holes worsen with age in adult. Central brain volume loss over 14d in adult. Loss of Applenhances, overexpressed Applpartially rescues mutant[81].


total number of fly neurodegeneration genes (DJ-1 and npc2 paralogs counted as one each):



number of fly genes with a mouse or human ortholog associated with neurodegeneration:




a  Degeneration in the CNS has not yet been demonstrated. The gene is included in the table due to widespread expression and/or a mammalian ortholog associated with neurodegeneration.

b  Heteroallelic combination: Atg7d77 removes a gene in one of Atg7‘s introns; Atg7d14 removes part of a neighboring gene [9].

c  Missense, conserved G>E, 98% homoplasmic. Strength of allele is unknown [11].

d  No data for fly. Prediction based on nature of protein.

e  For drd expression, query FlyAtlas for lwf (lot’s wife) [83].

f  UAS sequence in P insertion is in reverse orientation. Phenotypes and ena mRNA knockdown are Gal4-dependent [30].

g  The same allele was used by both groups. Lee et al. [38] report undetectable transcripts and loss of dopaminergic neurons in lrrke03680 flies. Phenotypes were not confirmed with a second reported allele, an imprecise P element excision removing 464bp from the 3′ end of the gene. Wang et al. [37] report no loss of dopaminergic neurons and detectable mutant transcripts that would yield a truncated protein lacking the kinase domain.

 BLAST with SNI peptide query against mouse returns 23 genes, significance (E-values) ranging from 7×10-11 to 8×10-4; against human returns 17 genes, E-values from 2×10-8 to 6×10-4. Mouse and human genes are 22-28% identical, 40-48% similar to sni.

 Not detected according to FlyAtlas. cDNA isolated from Schneider L2 cells. Mouse Mcoln3 cDNAs isolated from various postnatal tissues. Targeted expression of trpml in neurons, glia, or hemacytes/fat body of trpml1 mutants can rescue most phenotypes [79].
Last Update: 05/21/2009


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