Objective: To investigate the TFG pathology by analyzing transgenic mice expressing mutant TFG protein.
Background: It has been demonstrated that missense variants in TFG gene lead to motor neuron death, and broad clinical phenotypes have been reported, including hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), hereditary spastic paraplegia (HSP), and Charcot-Marie-Tooth disease (CMT). TFG has a biological role in protein sorting and trafficking. Immunohistopathological analyses showed neuronal inclusion formation with immunoreactivity of TFG and TDP-43 proteins. It is speculated that pathogenic mechanism might include aberrant function and proteinopathy of TFG. Electron microscopic study was performed in sciatic nerves.
Method: Transgenic mice (Tg) were created using the construct including hamster PrP promoter and either wild or mutant (P285L) human TFG (hTFG) cDNA. Immunohistopathological analyses were conducted using antibodies against TFG and ALS-related proteins, including TDP-43, OPTN, and FUS. Behavioral studies were also conducted to evaluate muscle strength.
Results: Mutant Tg showed progressive muscle waste at the age of 40 weeks and later, leading to death around 60 weeks of age. Atrophy of anterior horn cells accompanying cytoplasmic vacuolation was observed in the lumbar spinal cord. Neuronal inclusion formation with immunoreactivity of TFG and TDP-43 proteins were demonstrated in spinal motoneurons. Mislocalization of TDP-43 and OPTN proteins were also demonstrated. Loss of myelinated fibers and appearance of myelin ovoid were shown in biopsied sciatic nerves.
Conclusion: Tg expressing P285L-hTFG showed pathological features similar to those in patients. Inhibition of neuronal inclusion containing TFG might be therapeutic target.
References: Miyabayashi T, Ochiai T, Suzuki N, Aoki M, et al. A novel homozygous mutation of the TFG gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy. J Hum Genet. 64:171-176. 2019 Slosarek EL, Schuh AL, Pustova I, Johnson A, et al. Pathogenic TFG Mutations Underlying Hereditary Spastic Paraplegia Impair Secretory Protein Trafficking and Axon Fasciculation. Cell Rep. 24:2248-2260. 2018 Ishiura H, Sako W, Yoshida M, Kawarai T, et al. The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement. Am J Hum Genet. 912:320-9. 2012 Kawarai T, Morita M, Morigaki R, Fujita K, et al. Pathomechanisms of motor neuron death by mutant TFG. Rinsho Shinkeigaku. 23:1199. 2013 Murakami N, Imamura K, Izumi Y, Egawa N, et al. Proteasome impairment in neural cells derived from HMSN-P patient iPSCs. Mol Brain. 10:7. 2017
To cite this abstract in AMA style:T. Kawarai, A. Orlacchio, R. Kaji. Neuronal Inclusion Formation and Axonal Degeneration in Mutant TFG Transgenic Mice [abstract]. Mov Disord. 2020; 35 (suppl 1). https://www.mdsabstracts.org/abstract/neuronal-inclusion-formation-and-axonal-degeneration-in-mutant-tfg-transgenic-mice/. Accessed December 7, 2023.
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