Interplay of TRIM2 E3 Ubiquitin Ligase and ALIX/ESCRT Complex: Control of Developmental Plasticity During Early Neurogenesis

Abstract

Tripartite motif 2 (TRIM2) drives neurite outgrowth and polarization, is involved in axon specification, and confers neuroprotective functions during rapid ischemia. The mechanisms controlling neuronal cell fate determination and differentiation are fundamental for neural development. Here, we show that in Xenopus, trim2 knockdown affects primary neurogenesis and neural progenitor cell survival. Embryos also suffer from severe craniofacial malformation, a reduction in brain volume, and the loss of motor sensory function. Using a high-throughput LC-MS/MS approach with GST-Trim2 as bait, we pulled down ALG-2 interacting protein X (Alix) from Xenopus embryonic lysates. We demonstrate that the expression of trim2/TRIM2 and alix/ALIX overlap during larval development and on a cellular level in cell culture. Interestingly, trim2 morphants showed a clustering and apoptosis of neural progenitors, which are phenotypic hallmarks that are also observed in Alix KO mice. Therefore, we propose that the interaction of Alix and Trim2 plays a key role in the determination and differentiation of neural progenitors via the modulation of cell proliferation/apoptosis during neurogenesis.

Genetics of psycho-emotional well-being: genome-wide association study and polygenic risk score analysis

“…The ubiquitin ligase TRIM2 is involved in axon growth, polarization, and specification and has neuroprotection properties. Changes in TRIM2 function have been linked to progressive neurodegeneration in Alzheimer’s patients, while its variations have been associated with childhood-onset axonal neuropathy ( 65 ). Semaphorin 5B ( SEMA5B ) functions as a guidance cue and is essential for axon guidance and growth.…”

Expression and Role of TRIM2 in Human Diseases

“…We summarized the literature in nononcological research, as described above, concentrating mainly on the following aspects: (1) TRIM2 is regulated by the upstream miRNAs hsa-miR-18a-5p, hsa-miR-181b-5p, hsa-miR-181d-5p, and miR-181c and is associated with Pdcd6ip/Alix. In addition, TRIM2 plays a role in neuronal differentiation, axonal growth, and related nervous system diseases [18][19][20][21]. (2) TRIM2 inhibits Bim expression during rapid ischemic tolerance in the nervous system and then exerts a neuroprotective effect by regulating p42/ p44MAPK-dependent ubiquitination [14,22].…”

“…TRIM2 in Neurogenesis, Development, and Neuronal and Axonal Differentiation. Changes in TRIM2 expression have long been related to human nervous system diseases, and TRIM2 plays an important role in the nervous system [18]. Using a bioinformatics database, Su et al found that TRIM2 is an important gene that participates mainly in the regulation of the cell component tissue, axonogenesis, and cell morphogenesis during neuronal differentiation and is regulated by the upstream microRNAs (miRNAs) hsa-miR-18a-5p, hsa-miR-181b-5p, and hsa-miR-181d-5p [19].…”

“…Beyond the key role of TRIM2 in neuronal growth and regulation, Lokapally et al found in a study in Xenopus that TRIM2 was related to programmed cell death 6-interacting protein/apoptosis-related gene-2-interacting protein X (Pdcd6ip/Alix), which regulates nerve formation and development, controls cell proliferation and cell survival during early neural development, and participates in the determination and differentiation of neural progenitors; these findings provide evidence for a TRIM2-Alix interaction during early neural development [ 18 ].…”

Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental and epileptic encephalopathy to syndromic optic atrophy

“…Consistent with this hypothesis, bi-allelic loss-of-function (LoF) variants affecting multiple ESCRT subunits, including all three subunits of ESCRT-II, are not present in the general population, as observed in the Genome Aggregation Database (gnomAD). 16 To date, variants in a few of the genes encoding ESCRT subunits or associated proteins have been linked to Mendelian disorders, which are predominantly neurological diseases ( VPS37A , spastic paraplegia 53, autosomal-recessive [MIM: 614898 ]; 17 CHMP1A , pontocerebellar hypoplasia, type 8 [MIM: 614961 ]; 18 CHMP2B , frontotemporal dementia and/or amyotrophic lateral sclerosis 7 [MIM: 600795 ]; 19 PDCD6IP/ALIX , microcephaly 29, primary, autosomal-recessive [MIM: 620047 ]; 20 , 21 , 22 VPS4A , CIMDAG syndrome [MIM: 619273 ] 23 ).…”