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. Mimicking aspects of frontotemporal lobar degeneration and Lou Gehrig's disease in rats via TDP-43 overexpression. Mol Ther. 2009 Apr;17(4):607-13. PubMed.

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  1. The issue of whether overexpression of wild-type TDP-43 in rodent brain could be neurotoxic is neatly brought out in this paper from the group of Ronald Klein with senior authors Dennis Dickson and Mike Hutton. Using an adeno-associated virus type 9 (AAV9) vector for human TDP-43 expression by stereotactic injection into the rat substantia nigra (SN), Tatom and colleagues show that overexpression of human wild-type TDP-43 on its own can kill dopaminergic neurons in rats in a dose-dependent manner (Tatom et al., 2009).

    This approach is surely welcome at a time when many laboratories are struggling to get a decent TDP-43 expression in transgenic germlines. The reason why this is problematic is made apparent by this paper, where (roughly estimated) threefold wild-type TDP-43 overexpression almost completely wipes out the targeted neurons accompanied by neurodegeneration-related astro- and microgliosis. TDP-43 was selectively expressed in neurons as AAV9 has a natural neurotropism, perhaps due to the virus capsid (Bartlett et al., 1998); and while SN is chosen for sake of convenience allowing a rapid estimation of neuronal loss and behavior deficit, it is not without relevance. TDP-43 is naturally expressed in this brain region, and TDP-43 pathology is observed in the nigrostriatal pathway in a variety of neurodegenerative diseases.

    The descriptive neuropathology is fascinating to read. The transgenic protein predominantly homes to the neuronal nuclei, but in approximately 1 percent of the neurons, diffuse cytoplasmic TDP-43 accumulations are also observed. Occasionally, granular textures are observed that are indicative of pre-inclusion lesions as expected at 4 weeks of disease duration. One of the pathological hallmarks of diseased neurons in ALS and FTLD-TDP patients (FTLD-U in the old terminology) is redistribution of TDP-43 from its normal nuclear localization to the cytoplasm, where it is phosphorylated and ubiquitinated and forms insoluble aggregates.

    Interestingly, ubiquitin labeling was also observed in neuronal cytoplasm. It is not clear what proportion of neurons were labeled or whether it co-localized with TDP-43, but given that it was not observed in the contralateral, uninjected side, it is very likely that it is the transgenic TDP-43 protein that is ubiquitinated. It will be interesting to study whether TDP-43 is phosphorylated and/or cleaved into the disease-characteristic ~25-kDa C-terminal fragments. This would further strengthen the justification of trying to develop a rodent model of TDP-43 proteinopathy.

    At present the mechanism for TDP-43 dose-related neurodegeneration is unclear. Even so, considering the various important physiological functions of TDP-43 and a tight control on its expression levels, these data are not surprising. Of relevance to the majority of ALS and FTLD-TDP patients is that it is the wild-type TDP-43 protein that is accumulating and causing neurotoxicity. Given the speed at which these studies could be accomplished, it would be very interesting to study whether a similar overexpression of TDP-43 C-terminus recapitulates key features of TDP-43 proteinopathy in rat brain, as has been shown recently in cell cultures (Igaz et al., 2009).

    Lastly, having an AAV-based TDP-43 rodent model is not a substitute for a rodent model with stable germline transmission achieved by either a constitutive or inducible expression system. That amongst all would allow us to understand which neurons are more vulnerable to TDP-43 gene dosage. But until these models are developed, expression of TDP-43 by AAV-mediated somatic cell transfer approaches will continue to shed light on TDP-43 mediated disease mechanisms.

    References:

    . Selective and rapid uptake of adeno-associated virus type 2 in brain. Hum Gene Ther. 1998 May 20;9(8):1181-6. PubMed.

    . Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies. J Biol Chem. 2009 Mar 27;284(13):8516-24. PubMed.

    . Mimicking aspects of frontotemporal lobar degeneration and Lou Gehrig's disease in rats via TDP-43 overexpression. Mol Ther. 2009 Apr;17(4):607-13. PubMed.