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Cited by 81Genetics and Neurodevelopmental DisordersMitochondrial Function and PathologyAutophagy in Disease and Therapy

Mitochondrial dysfunction and oxidative stress contribute to cognitive and motor impairment in FOXP1 syndrome

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Wang, Jing, Fröhlich, Henning, Torres, Felipe Bodaleo, Silva, Rangel Leal, Poschet, Gernot, Agarwal, Amit, Rappold, Gudrun A.·2022·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2112852119PMC PMC8872729

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Abstract

Significance: FOXP1 haploinsufficiency underlies cognitive and motor impairments in individuals with FOXP1 syndrome. Here, we show that mice lacking one Foxp1 copy exhibit similar behavioral deficits, which may be caused by striatal dysfunction. Indeed, Foxp1 +/− striatal medium spiny neurons display reduced neurite branching, and we show altered mitochondrial biogenesis and dynamics; increased mitophagy; reduced mitochondrial membrane potential, structure, and motility; and elevated oxygen species in the striatum of these animals. As FOXP1 is highly conserved, our data strongly suggest that mitochondrial dysfunction and excessive oxidative stress contribute to the motor and cognitive impairments seen in individuals with FOXP1 syndrome. Thus, mitochondrial homeostasis is critical for normal development and can explain deficits in neurodevelopmental disorders.

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  • Notable perturbation-specific gene ontology terms include ribosome assembly (SETD5), mitochondrion organization (FOXP1), lipid homoeostasis (IRF2BPL), autophagosome maturation (KAT2B), and cilium development (MECP2).

    “Some notable examples include the gene ontology terms ribosome assembly (SETD5 perturbation)36, mitochondrion organization (FOXP1 perturbation)37, lipid homoeostasis (IRF2BPL perturbation)38, autophagosome maturation (KAT2B perturbation)39 and cilium development (MECP2 perturbation)40.”

    From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [37]

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  1. [2]P. M. Siper, Prospective investigation of FOXP1 syndrome. Mol. Autism 8, 57 (2017). 29090079 PMC5655854
  2. [4]S. Li, J. Weidenfeld, E. E. Morrisey, Transcriptional and DNA binding activity of the Foxp1/2/4 family is modulated by heterotypic and homotypic protein interactions. Mol. Cell. Biol. 24, 809– 822 (2004). 14701752 PMC343786
  3. [5]E. Mendoza, C. Scharff, Protein-protein interaction among the FoxP family members and their regulation of two target genes, VLDLR and CNTNAP2 in the zebra finch song system. Front. Mol. Neurosci. 10, 112 (2017). 28507505 PMC5410569
  4. [6]C. S. Lai, S. E. Fisher, J. A. Hurst, F. Vargha-Khadem, A. P. Monaco, A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413, 519– 523 (2001). 11586359
  5. [7]M. Co, A. G. Anderson, G. Konopka, FOXP transcription factors in vertebrate brain development, function, and disorders. Wiley Interdiscip. Rev. Dev. Biol. 9, e375 (2020). 31999079 PMC8286808
  6. [8]B. Wang, Foxp1 regulates cardiac outflow tract, endocardial cushion morphogenesis and myocyte proliferation and maturation. Development 131, 4477– 4487 (2004). 15342473
  7. [9]D. J. Araujo, FoxP1 orchestration of ASD-relevant signaling pathways in the striatum. Genes Dev. 29, 2081– 2096 (2015). 26494785 PMC4617974
  8. [10]H. Fröhlich, Gastrointestinal dysfunction in autism displayed by altered motility and achalasia in Foxp1 +/- mice. Proc. Natl. Acad. Sci. U.S.A. 116, 22237– 22245 (2019). 31611379 PMC6825283
  9. [11]I. Meerschaut, FOXP1-related intellectual disability syndrome: A recognisable entity. J. Med. Genet. 54, 613– 623 (2017). 28735298
  10. [12]C. Bacon, Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour. Mol. Psychiatry 20, 632– 639 (2015). 25266127 PMC4419151
  11. [13]N. Usui, Foxp1 regulation of neonatal vocalizations via cortical development. Genes Dev. 31, 2039– 2055 (2017). 29138280 PMC5733496
  12. [15]A. G. Anderson, A. Kulkarni, M. Harper, G. Konopka, Single-cell analysis of Foxp1-driven mechanisms essential for striatal development. Cell Rep. 30, 3051– 3066.e7 (2020). 32130906 PMC7137930
  13. [16]O. Kann, R. Kovács, Mitochondria and neuronal activity. Am. J. Physiol. Cell Physiol. 292, C641– C657 (2007). 17092996
  14. [17]M. Khacho, R. S. Slack, Mitochondrial dynamics in the regulation of neurogenesis: From development to the adult brain. Dev. Dyn. 247, 47– 53 (2018). 28643345
  15. [18]Z. Li, K. Okamoto, Y. Hayashi, M. Sheng, The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119, 873– 887 (2004). 15607982
  16. [19]D. A. Rossignol, R. E. Frye, Mitochondrial dysfunction in autism spectrum disorders: A systematic review and meta-analysis. Mol. Psychiatry 17, 290– 314 (2012). 21263444 PMC3285768
  17. [20]A. Valiente-Pallejà, Genetic and clinical evidence of mitochondrial dysfunction in autism spectrum disorder and intellectual disability. Hum. Mol. Genet. 27, 891– 900 (2018). 29340697
  18. [21]A. K. Le Fevre, FOXP1 mutations cause intellectual disability and a recognizable phenotype. Am. J. Med. Genet. A. 161A, 3166– 3175 (2013). 24214399
  19. [22]R. N. Krajeski, A. Macey-Dare, F. van Heusden, F. Ebrahimjee, T. J. Ellender, Dynamic postnatal development of the cellular and circuit properties of striatal D1 and D2 spiny projection neurons. J. Physiol. 597, 5265– 5293 (2019). 31531863 PMC6900874
  20. [23]R. T. Peixoto, W. Wang, D. M. Croney, Y. Kozorovitskiy, B. L. Sabatini, Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B(-/-) mice. Nat. Neurosci. 19, 716– 724 (2016). 26928064 PMC4846490
  21. [24]Y. Zou, Forkhead box P1 (FOXP1) transcription factor regulates hepatic glucose homeostasis. J. Biol. Chem. 290, 30607– 30615 (2015). 26504089 PMC4683280
  22. [26]D. Lettieri-Barbato, FoxO1 localizes to mitochondria of adipose tissue and is affected by nutrient stress. Metabolism 95, 84– 92 (2019). 30974111
  23. [27]Z. Gan, T. Fu, D. P. Kelly, R. B. Vega, Skeletal muscle mitochondrial remodeling in exercise and diseases. Cell Res. 28, 969– 980 (2018). 30108290 PMC6170448
  24. [28]P. Puigserver, Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1α interaction. Nature 423, 550– 555 (2003). 12754525
  25. [29]B. Sheng, Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer’s disease. J. Neurochem. 120, 419– 429 (2012). 22077634 PMC3253532
  26. [30]R. Ventura-Clapier, A. Garnier, V. Veksler, Transcriptional control of mitochondrial biogenesis: The central role of PGC-1alpha. Cardiovasc. Res. 79, 208– 217 (2008). 18430751
  27. [31]H. Lee, S. B. Smith, Y. Yoon, The short variant of the mitochondrial dynamin OPA1 maintains mitochondrial energetics and cristae structure. J. Biol. Chem. 292, 7115– 7130 (2017). 28298442 PMC5409478
  28. [32]A. Jahani-Asl, R. S. Slack, The phosphorylation state of Drp1 determines cell fate. EMBO Rep. 8, 912– 913 (2007). 17906671 PMC2002565
  29. [34]S. Rodriguez-Enriquez, I. Kim, R. T. Currin, J. J. Lemasters, Tracker dyes to probe mitochondrial autophagy (mitophagy) in rat hepatocytes. Autophagy 2, 39– 46 (2006). 16874071 PMC4007489
  30. [36]Y. Sun, miR-142 controls metabolic reprogramming that regulates dendritic cell activation. J. Clin. Invest. 129, 2029– 2042 (2019). 30958798 PMC6486330
  31. [38]Z. Yin, Structural basis for a complex I mutation that blocks pathological ROS production. Nat. Commun. 12, 707 (2021). 33514727 PMC7846746
  32. [39]F. de Nigris, Oxidation-sensitive mechanisms, vascular apoptosis and atherosclerosis. Trends Mol. Med. 9, 351– 359 (2003). 12928037
  33. [40]M. P. Mattson, Neuronal life-and-death signaling, apoptosis, and neurodegenerative disorders. Antioxid. Redox Signal. 8, 1997– 2006 (2006). 17034345
  34. [41]S. S. Correia, A. G. McGrath, A. Lee, A. M. Graybiel, K. A. Goosens, Amygdala-ventral striatum circuit activation decreases long-term fear. eLife 5, e12669 (2016). 27671733 PMC5039029
  35. [42]S. Hormigo, G. Vega-Flores, M. A. Castro-Alamancos, Basal ganglia output controls active avoidance behavior. J. Neurosci. 36, 10274– 10284 (2016). 27707965 PMC5050325
  36. [43]P. J. Fernandez-Marcos, J. Auwerx, Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am. J. Clin. Nutr. 93, 884S– 890S (2011). 21289221 PMC3057551
  37. [44]R. Cartoni, Mitofusins 1/2 and ERRalpha expression are increased in human skeletal muscle after physical exercise. J. Physiol. 567, 349– 358 (2005). 15961417 PMC1474174
  38. [45]I. Kang, C. T. Chu, B. A. Kaufman, The mitochondrial transcription factor TFAM in neurodegeneration: Emerging evidence and mechanisms. FEBS Lett. 592, 793– 811 (2018). 29364506 PMC5851836
  39. [46]D. P. Kelly, R. C. Scarpulla, Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 18, 357– 368 (2004). 15004004
  40. [47]Z. Wu, Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115– 124 (1999). 10412986
  41. [48]O. J. Martin, A role for peroxisome proliferator-activated receptor γ coactivator-1 in the control of mitochondrial dynamics during postnatal cardiac growth. Circ. Res. 114, 626– 636 (2014). 24366168 PMC4061768
  42. [49]Y. Ge, Two forms of Opa1 cooperate to complete fusion of the mitochondrial inner-membrane. eLife 9, e50973 (2020). 31922487 PMC7299343
  43. [50]C. R. Chang, C. Blackstone, Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J. Biol. Chem. 282, 21583– 21587 (2007). 17553808
  44. [51]L. C. Gomes, L. Scorrano, High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy. Biochim. Biophys. Acta 1777, 860– 866 (2008). 18515060
  45. [53]S. Pickles, P. Vigié, R. J. Youle, Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr. Biol. 28, R170– R185 (2018). 29462587 PMC7255410
  46. [54]D. G. Hardie, Minireview: The AMP-activated protein kinase cascade: The key sensor of cellular energy status. Endocrinology 144, 5179– 5183 (2003). 12960015
  47. [55]M. Yamamoto, Regulation of oxidative stress by the anti-aging hormone klotho. J. Biol. Chem. 280, 38029– 38034 (2005). 16186101 PMC2515369
  48. [56]W. Xiao, R. S. Wang, D. E. Handy, J. Loscalzo, NAD(H) and NADP(H) redox couples and cellular energy metabolism. Antioxid. Redox Signal. 28, 251– 272 (2018). 28648096 PMC5737637
  49. [57]X. Cao, L. Wu, J. Zhang, M. Dolg, Density functional studies of coenzyme NADPH and its oxidized form NADP+: Structures, UV-Vis spectra, and the oxidation mechanism of NADPH. J. Comput. Chem. 41, 305– 316 (2020). 31713255
  50. [58]Q. Chen, The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction. Cell Death Differ. 10, 323– 334 (2003). 12700632 PMC1196205
  51. [59]D. H. Geschwind, P. Levitt, Autism spectrum disorders: Developmental disconnection syndromes. Curr. Opin. Neurobiol. 17, 103– 111 (2007). 17275283
  52. [60]A. Anitha, Brain region-specific altered expression and association of mitochondria-related genes in autism. Mol. Autism 3, 12 (2012). 23116158 PMC3528421
  53. [61]R. E. Frye, Mitochondrial dysfunction may explain symptom variation in Phelan–McDermid syndrome. Sci. Rep. 6, 19544 (2016). 26822410 PMC4731780
  54. [63]N. Cheng, J. M. Rho, S. A. Masino, Metabolic dysfunction underlying autism spectrum disorder and potential treatment approaches. Front. Mol. Neurosci. 10, 34 (2017). 28270747 PMC5318388
  55. [64]A. K. Kanellopoulos, Aralar sequesters GABA into hyperactive mitochondria, causing social behavior deficits. Cell 180, 1178– 1197.e20 (2020). 32200800
  56. [65]V. Costa, L. Scorrano, Shaping the role of mitochondria in the pathogenesis of Huntington’s disease. EMBO J. 31, 1853– 1864 (2012). 22446390 PMC3343341
  57. [66]R. J. Ferrante, N. W. Kowall, E. P. Richardson Jr,, Proliferative and degenerative changes in striatal spiny neurons in Huntington’s disease: A combined study using the section-Golgi method and calbindin D28k immunocytochemistry. J. Neurosci. 11, 3877– 3887 (1991). 1836019 PMC6575286
  58. [67]A. S. C. Louis Sam Titus, Reduced expression of Foxp1 as a contributing factor in Huntington’s disease. J. Neurosci. 37, 6575– 6587 (2017). 28550168 PMC5511885
  59. [68]B. Tang, Forkhead box protein p1 is a transcriptional repressor of immune signaling in the CNS: Implications for transcriptional dysregulation in Huntington disease. Hum. Mol. Genet. 21, 3097– 3111 (2012). 22492998 PMC3384380
  60. [70]L. Cui, Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127, 59– 69 (2006). 17018277
  61. [72]S. Melzer, Distinct corticostriatal GABAergic neurons modulate striatal output neurons and motor activity. Cell Rep. 19, 1045– 1055 (2017). 28467898 PMC5437725
  62. [73]A. G. Carter, B. L. Sabatini, State-dependent calcium signaling in dendritic spines of striatal medium spiny neurons. Neuron 44, 483– 493 (2004). 15504328
  63. [74]D. L. Rousso, Z. B. Gaber, D. Wellik, E. E. Morrisey, B. G. Novitch, Coordinated actions of the forkhead protein Foxp1 and Hox proteins in the columnar organization of spinal motor neurons. Neuron 59, 226– 240 (2008). 18667151 PMC2547125
  64. [75]D. J. Socci, K. B. Bjugstad, H. C. Jones, J. V. Pattisapu, G. W. Arendash, Evidence that oxidative stress is associated with the pathophysiology of inherited hydrocephalus in the H-Tx rat model. Exp. Neurol. 155, 109– 117 (1999). 9918710
  65. [76]N. Chenouard, J. Buisson, I. Bloch, P. Bastin, J.-C. Olivo-Marin, “Curvelet analysis of kymograph for tracking bi-directional particles in fluorescence microscopy images” in 2010 IEEE International Conference on Image Processing (2010), pp. 3657– 3660.
  66. [77]F. de Chaumont, Icy: An open bioimage informatics platform for extended reproducible research. Nat. Methods 9, 690– 696 (2012). 22743774
  67. [78]S. Berg, ilastik: Interactive machine learning for (bio)image analysis. Nat. Methods 16, 1226– 1232 (2019). 31570887

Authors
Wang, J., Fröhlich, H., Torres, F. B., Silva, R. L., Poschet, G., Agarwal, A., & Rappold, G. A.
Affiliations
  • University Hospital Heidelberg (DE)
  • Chica and Heinz Schaller Foundation (DE)
  • Heidelberg University (DE)
Corresponding author
Rappold, Gudrun A.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2022-02-14
Volume
119
Issue
8
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2112852119
PMC
PMC8872729
OpenAlex
W4220792642
Cited by
81
References
90
Citations by year
2026: 12 · 2025: 29 · 2024: 28 · 2023: 8 · 2022: 4
FWCI
10.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Chinese Scholarship Council (#201708230108)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
mitochondrial dysfunction, oxidative stress, striatal medium spiny neurons, mitochondrial biogenesis, mitochondrial dynamics, mitophagy, mitochondrial membrane potential, mitochondrial motility, oxygen species, cognitive impairment, motor impairment, neurodevelopmental disorders, mouse model
MeSH terms
Autism Spectrum Disorder, Motor Disorders, Animals, Autistic Disorder, Cognition, Disease Models, Animal, Intellectual Disability, Mice, Inbred C57BL, Mitochondria, Motor Activity, Repressor Proteins, Oxidative Stress, Mice, Forkhead Transcription Factors, Neurogenesis, Haploinsufficiency, Neurodevelopmental Disorders

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