Table 1.
Neurodegenerative disorders associated with genetic intervention of autophagy in mice.
| Setting | Genetic intervention | Effects on disease phenotype | Ref. |
|---|---|---|---|
| Alzheimer disease | Myeloid cell‐specific deletion of Trim16 | Exacerbated endomembrane damage post‐infection with Mycobacterium tuberculosis | Jia et al (2020) |
| Alzheimer disease | Whole‐body deletion of Sqstm1/p62 | Accumulation of hyperphosphorylated MAPT/tau and neurodegeneration | Ramesh Babu et al (2008) |
| Alzheimer disease | Whole‐body deletion of Nrf2 | Aberrant accumulation of phosphorylated and sarkosyl‐insoluble tau protein | Jo et al (2014) |
| Alzheimer disease | Conditional excitatory neuron‐specific deletion of Atg7 | Reduced extracellular Aβ plaque burden, linked to cognitive dysfunction in APP transgenic mice | Nilsson et al (2013) |
| Alzheimer disease | Whole‐body deletion of Nrbf2 | Impaired cognitive fitness and increased Aβ plaque accumulation | Lachance et al (2019) |
| Alzheimer disease | Whole‐body deletion of Trem2 | Impaired metabolic fitness and increased accumulation of autophagic vesicles in the microglia of 5XFAD mice | Ulland et al (2017) |
| Alzheimer disease | Conditional myeloid cell‐specific deletion of Atg5 or Rubcn | Exacerbated Aβ plaque accumulation and inflammation within the hippocampus of young 5xFAD mice | Heckmann et al (2019) |
| Alzheimer disease | Whole‐body deletion of Atg16LΔWD | Exacerbated Aβ plaque accumulation, neuroinflammation and Tau hyperphosphorylation | Heckmann et al (2020) |
| Alzheimer disease | Neuron‐specific deletion of Lamp2 | Exacerbated Tau acetylation, extraneuronal release and propagation, linked to accelerated disease progression | Bourdenx et al (2021), Caballero et al (2021) |
| Amyotrophic lateral sclerosis | Whole‐body deletion of Epg5 | Muscle denervation, myofiber atrophy, late‐onset progressive paralysis, and reduced survival | Zhao et al (2013) |
| Amyotrophic lateral sclerosis | Conditional motoneuron‐specific deletion of Tbk1 | Accelerated early disease onset in SOD1G93A mice, linked to increased accumulation of ubiquitinated aggregates | Gerbino et al (2020) |
| Amyotrophic lateral sclerosis | Whole‐body knock‐in of mutant Tbk1G217R or Tbk1R228H | Accelerated early disease onset but extended lifespan in SOD1G93A mice, linked to reduced microglia IFN response | Gerbino et al (2020) |
| Amyotrophic lateral sclerosis | Whole‐body deletion of Grn | Exacerbated symptomatology linked to increased accumulation of pathological TDP‐43 in neurons | Chang et al (2017) |
| Amyotrophic lateral sclerosis | Conditional neuron‐specific deletion of Xbp1 | Reduced disease onset in SOD1G93A mice after inducing autophagy in motoneurons | Hetz et al (2009) |
| Amyotrophic lateral sclerosis | AAV‐mediated hippocampal‐specific deletion of C9orf72 | Exacerbated cognitive and motor deficits, hippocampal neuron loss, and DPR protein accumulation, after autophagy inhibition | Zhu et al (2020) |
| Amyotrophic lateral sclerosis | Whole‐body allelic loss of Becn1 | Increased lifespan of mutant SOD1 transgenic mice | Nassif et al (2014) |
| Focal malformations of cortical development | Brain somatic mutations in MTOR | Cortical abnormalities that are highly associated with medically intractable epilepsy, intellectual disability, developmental delay, and autism‐spectrum disorders | Park et al (2018) |
| Axon growth | POMC neuron‐specific deletion of Atg7 | Abnormal development of POMC neuronal projections, associated with metabolic dysregulations | Coupe et al (2012) |
| Cognitive fitness | shRNA‐dependent hippocampal‐specific deletion of Becn1, Atg12 or Rb1cc1 | Impaired capacity to generate novel memories | Glatigny et al (2019) |
| Food intake and energy balance | AgRP neuron‐specific deletion of Atg7 | Increased neuronal lipid accumulation, associated with altered energy balance and food intake after starvation | Kaushik et al (2011) |
| Huntington disease | Conditional whole‐body deletion of WDFY3/ALFY | Accumulation of proteinaceous deposits, linked to accelerated onset and progression of Huntington disease pathogenesis | Fox et al (2020) |
| Ischemic brain damage | Whole‐body allelic loss of Sod2 | Increased infarct volume under hyperglycemic conditions, linked to increased oxidative DNA damage | Mehta et al (2011) |
| Ischemic brain damage | Neuron‐specific deletion of Atg7 | Complete protection from neonatal hypoxic/ischemic brain injury | Koike et al (2008), Xie et al (2016) |
| Nerve injury | Schwann cell‐specific deletion of Atg7 | Delayed myelin degradation and generation of repair cells after injury | Gomez‐Sanchez et al (2015) |
| Neurodegeneration | Neural cell‐specific deletion of Atg5 | Development of progressive deficits in motor function linked to cytoplasmic inclusion body accumulation in neurons | Hara et al (2006) |
| Neurodegeneration | Conditional CNS‐specific deletion of Atg7 | Behavioral defects and premature death, linked to massive neuronal loss and cytoplasmic inclusion body accumulation | Komatsu et al (2006) |
| Neurodegeneration | Conditional radial glial cell‐specific deletion of Rb1cc1 | Progressive loss of NSCs pool and impaired neuronal differentiation in the postnatal brain | Wang et al (2013) |
| Neurodegeneration | Conditional CNS‐specific deletion of Wdr45 | Reduced motor coordination, impaired learning and memory, and extensive axon swelling | Zhao et al (2015) |
| Neurodegeneration | Conditional neuron‐specific deletion of Wipi3 | Behavioral defects and cerebellar neuronal loss after non‐canonical autophagy inhibition | Yamaguchi et al (2020) |
| Neurodegeneration | Conditional telencephalon‐specific deletion of Vps15 | Severe progressive cortical atrophy associated with caspase‐induced apoptosis | Gstrein et al (2018) |
| Neurodegeneration | Whole‐body knock‐in of hypomorphic Atg16l1 | Developmental retention due to delayed differentiation of stem cells in the brain | Wu et al (2016) |
| Neurodegeneration | Conditional NSC‐specific co‐deletion of FoxO1, FoxO3 and FoxO4 | Initial proliferation of neural progenitor cells in early postnatal life, followed by NSC pool decline in adult brains | Paik et al (2009) |
| Neurodegeneration | Purkinje cell‐specific deletion of Atg7 | Progressive cell autonomous dystrophy and degeneration of the axon terminals | Komatsu et al (2007) |
| Neurodegeneration | Whole‐body deletion of TAX1BP1 | Aberrant accumulation of high molecular weight ubiquitin conjugates and lipofuscin | Sarraf et al (2020) |
| Neuropathies | Whole‐body deletion of Fam134b | Degeneration of sensory neurons after inhibition of ER‐phagy | Khaminets et al (2015) |
| Neuropathies | Whole‐body deletion of Tecpr2 | Exacerbated age‐dependent behavioral aberrations and neuroaxonal dystrophy, after accumulation of autophagosomes | Tamim‐Yecheskel et al (2020) |
| Neurotransmission | Post‐mitotic excitatory neuron‐specific deletion of Atg5 | Increased accumulation of tubular ER in axons, linked to increased excitatory neurotransmission and premature death | Kuijpers et al (2021) |
| Parkinson disease | Microglia‐specific deletion of Atg7 | Increased α‐synuclein accumulation and neurodegeneration | Choi et al (2020) |
| Parkinson disease | Whole‐body deletion of Rubcn | Reduced α‐synuclein accumulation in the brain, linked to reduced age‐related interstitial fibrosis in kidney | Nakamura et al (2019) |
| Parkinson disease | Conditional SN neuron‐specific deletion of Atg7 | Resistance to retrograde axonal degeneration | Cheng et al (2011) |
| Parkinson disease |
AAV‐mediated SN‐specific knock‐in of dominant‐negative Ulk1 |
Attenuated MPTP‐induced axonal neurodegeneration | Balke et al (2020) |
| Parkinson disease | Whole‐body deletion of Prkn | Impaired striatal neural plasticity, linked to increased sensitivity to oxidative damage and mitochondrial dysfunction (exacerbated in Mutator mice but rescued by loss of STING) | Goldberg et al (2003), Palacino et al (2004), Kitada et al (2009), Pickrell et al (2015), Sliter et al (2018) |
| Parkinson disease | Whole‐body deletion of Pink1 | Increased sensitivity to oxidative damage and mitochondrial dysfunction | Gautier et al (2008) |
AAV, adeno‐associated viral vector; AgRP, agouti‐related protein; APP, amyloid precursor protein; CNS, central nervous system; DPR, dipeptide‐repeated; MPTP, 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine; NSCS, neural stem cell; OGD, oxygen glucose deprivation; POMC, proopiomelanocortin; SN, substantia nigra; TDP‐43, transactive response DNA‐binding protein of 43 kD.