The P75 Neurotrophin Receptor Can Induce Autophagy and Death of Cerebellar Purkinje Neurons

Overview

Journal J Neurosci

Specialty Neurology

Date 2004 May 14

PMID 15140920

Citations 44

Authors

Maria L Florez-McClure

Daniel A Linseman

Charleen T Chu

Phil A Barker

Ron J Bouchard

Shoshona S Le

Tracey A Laessig

Kim A Heidenreich

Affiliations

Soon will be listed here.

Abstract

The cellular mechanisms underlying Purkinje neuron death in various neurodegenerative disorders of the cerebellum are poorly understood. Here we investigate an in vitro model of cerebellar neuronal death. We report that cerebellar Purkinje neurons, deprived of trophic factors, die by a form of programmed cell death distinct from the apoptotic death of neighboring granule neurons. Purkinje neuron death was characterized by excessive autophagic-lysosomal vacuolation. Autophagy and death of Purkinje neurons were inhibited by nerve growth factor (NGF) and were activated by NGF-neutralizing antibodies. Although treatment with antisense oligonucleotides to the p75 neurotrophin receptor (p75ntr) decreased basal survival of cultured cerebellar neurons, p75ntr-antisense decreased autophagy and completely inhibited death of Purkinje neurons induced by trophic factor withdrawal. Moreover, adenoviral expression of a p75ntr mutant lacking the ligand-binding domain induced vacuolation and death of Purkinje neurons. These results suggest that p75ntr is required for Purkinje neuron survival in the presence of trophic support; however, during trophic factor withdrawal, p75ntr contributes to Purkinje neuron autophagy and death. The autophagic morphology resembles that found in neurodegenerative disorders, suggesting a potential role for this pathway in neurological disease.

Citing Articles

Building better brains: the pleiotropic function of neurotrophic factors in postnatal cerebellar development.

Boxy P, Nykjaer A, Kisiswa L Front Mol Neurosci. 2023; 16:1181397.

PMID: 37251644 PMC: 10213292. DOI: 10.3389/fnmol.2023.1181397.

Role of Autophagy in HIV-1 and Drug Abuse-Mediated Neuroinflammaging.

Sil S, Thangaraj A, Oladapo A, Hu G, Kutchy N, Liao K Viruses. 2023; 15(1).

PMID: 36680084 PMC: 9866731. DOI: 10.3390/v15010044.

Neurotrophins as Key Regulators of Cell Metabolism: Implications for Cholesterol Homeostasis.

Colardo M, Martella N, Pensabene D, Siteni S, Di Bartolomeo S, Pallottini V Int J Mol Sci. 2021; 22(11).

PMID: 34073639 PMC: 8198482. DOI: 10.3390/ijms22115692.

Cerebellar Calcium-Binding Protein and Neurotrophin Receptor Defects in Down Syndrome and Alzheimer's Disease.

Miguel J, Perez S, Malek-Ahmadi M, Mufson E Front Aging Neurosci. 2021; 13:645334.

PMID: 33776745 PMC: 7994928. DOI: 10.3389/fnagi.2021.645334.

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Klionsky D, Abdel-Aziz A, Abdelfatah S, Abdellatif M, Abdoli A, Abel S Autophagy. 2021; 17(1):1-382.

PMID: 33634751 PMC: 7996087. DOI: 10.1080/15548627.2020.1797280.

References

Wang K, Kim J, Sivasankaran R, Segal R, He Z . P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature. 2002; 420(6911):74-8. DOI: 10.1038/nature01176. View

Lemasters J, Qian T, He L, Kim J, Elmore S, Cascio W . Role of mitochondrial inner membrane permeabilization in necrotic cell death, apoptosis, and autophagy. Antioxid Redox Signal. 2002; 4(5):769-81. DOI: 10.1089/152308602760598918. View

Cataldo A, Hamilton D, Barnett J, Paskevich P, Nixon R . Properties of the endosomal-lysosomal system in the human central nervous system: disturbances mark most neurons in populations at risk to degenerate in Alzheimer's disease. J Neurosci. 1996; 16(1):186-99. PMC: 6578706. View

Frade J, Rodriguez-Tebar A, Barde Y . Induction of cell death by endogenous nerve growth factor through its p75 receptor. Nature. 1996; 383(6596):166-8. DOI: 10.1038/383166a0. View

Barrett G, Georgiou A . The low-affinity nerve growth factor receptor p75NGFR mediates death of PC12 cells after nerve growth factor withdrawal. J Neurosci Res. 1996; 45(2):117-28. DOI: 10.1002/(SICI)1097-4547(19960715)45:2<117::AID-JNR4>3.0.CO;2-D. View

Carter B, Dobrowsky R, Chao M . Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature. 1996; 383(6602):716-9. DOI: 10.1038/383716a0. View

Cheema S, Barrett G, Bartlett P . Reducing p75 nerve growth factor receptor levels using antisense oligonucleotides prevents the loss of axotomized sensory neurons in the dorsal root ganglia of newborn rats. J Neurosci Res. 1996; 46(2):239-45. DOI: 10.1002/(SICI)1097-4547(19961015)46:2<239::AID-JNR12>3.0.CO;2-Y. View

Lasmezas C, Deslys J, Robain O, Jaegly A, Beringue V, Peyrin J . Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science. 1997; 275(5298):402-5. DOI: 10.1126/science.275.5298.402. View

Anglade P, Vyas S, Herrero M, Michel P, Marquez J, Mouatt-Prigent A . Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. Histol Histopathol. 1997; 12(1):25-31. View

10.

Majdan M, Lachance C, Gloster A, Aloyz R, Zeindler C, Bamji S . Transgenic mice expressing the intracellular domain of the p75 neurotrophin receptor undergo neuronal apoptosis. J Neurosci. 1997; 17(18):6988-98. PMC: 6573268. View

11.

Zuo J, De Jager P, Takahashi K, Jiang W, Linden D, Heintz N . Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene. Nature. 1997; 388(6644):769-73. DOI: 10.1038/42009. View

12.

Jia L, Dourmashkin R, Allen P, Gray A, Newland A, Kelsey S . Inhibition of autophagy abrogates tumour necrosis factor alpha induced apoptosis in human T-lymphoblastic leukaemic cells. Br J Haematol. 1997; 98(3):673-85. DOI: 10.1046/j.1365-2141.1997.2623081.x. View

13.

Yaar M, Zhai S, Pilch P, Doyle S, Eisenhauer P, Fine R . Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer's disease. J Clin Invest. 1997; 100(9):2333-40. PMC: 508430. DOI: 10.1172/JCI119772. View

14.

Condorelli D, DellAlbani P, Timmusk T, Mudo G, Belluardo N . Differential regulation of BDNF and NT-3 mRNA levels in primary cultures of rat cerebellar neurons. Neurochem Int. 1998; 32(1):87-91. DOI: 10.1016/s0197-0186(97)00038-7. View

15.

Mount H, Elkabes S, Dreyfus C, Black I . Differential involvement of metabotropic and p75 neurotrophin receptors in effects of nerve growth factor and neurotrophin-3 on cultured Purkinje cell survival. J Neurochem. 1998; 70(3):1045-53. DOI: 10.1046/j.1471-4159.1998.70031045.x. View

16.

Barrett G, Bartlett P . The p75 nerve growth factor receptor mediates survival or death depending on the stage of sensory neuron development. Proc Natl Acad Sci U S A. 1994; 91(14):6501-5. PMC: 44230. DOI: 10.1073/pnas.91.14.6501. View

17.

Fessatidis I, Thomas V, Shore D, Hunt R, Weller R . Neuropathological features of profoundly hypothermic circulatory arrest: an experimental study in the pig. Cardiovasc Surg. 1993; 1(2):155-60. View

18.

Torres-Aleman I, Pons S, Arevalo M . The insulin-like growth factor I system in the rat cerebellum: developmental regulation and role in neuronal survival and differentiation. J Neurosci Res. 1994; 39(2):117-26. DOI: 10.1002/jnr.490390202. View

19.

Zanjani H, Herrup K, Guastavino J, Delhaye-Bouchaud N, Mariani J . Developmental studies of the inferior olivary nucleus in staggerer mutant mice. Brain Res Dev Brain Res. 1994; 82(1-2):18-28. DOI: 10.1016/0165-3806(94)90144-9. View

20.

Biederbick A, Kern H, Elsasser H . Monodansylcadaverine (MDC) is a specific in vivo marker for autophagic vacuoles. Eur J Cell Biol. 1995; 66(1):3-14. View