TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration

Abstract

dementia ͉ motor neuron disease ͉ neurodegeneration ͉ protein aggregation F TLD is a relatively common cause of dementia among patients with onset before 65, typically manifesting with behavioral changes or language impairment due to degeneration of subpopulations of cortical neurons in the frontal, temporal and insular regions (1). By contrast, ALS presents with muscle weakness and spasticity due to degeneration of motor neurons in both layer 5 of cortex and in the spinal cord, resulting in death from respiratory failure in 3-5 years (2, 3). Interestingly, approximately 20% of patients with ALS also develop FTLD, and approximately 15% of FLTD patients also develop ALS (4, 5).The discovery that TDP-43 is present in cytoplasmic aggregates in both ALS and FTLD-U provided evidence that the two disorders may share a common underlying mechanism (6). TDP-43 is an RNA/DNA binding protein, implicated in regulation of alternative splicing of messenger RNA, RNA stability, and transcriptional control (7). The concept that TDP-43 can play a direct role in neurodegeneration was strengthened by recent reports that dominantly inherited missense mutations in TDP-43 are found in patients with familial ALS (8-12). Mutations in TDP-43 associated with ALS cluster in the C-terminal glycine-rich region, which is involved in protein-protein interactions between TDP-43 and other heterogeneous nuclear ribonuclear proteins (hnRNPs) (13). Furthermore, C-terminal fragments of TDP-43 are observed selectively in ALS and FTLD-U tissues, suggesting that proteolytic cleavage of TDP-43 leads to protein aggregation or another toxic property (6). Therefore, several putative mechanisms of TDP-43 induced neurodegeneration are currently under investigation, including toxic protein aggregation, and/or disruption of normal TDP-43 RNA/DNA binding protein function. Here we report a mouse model of TDP-43 induced neurodegeneration which recapitulates key features of ALS and FTLD-U, including ubiquitin aggregate pathology with selective vulnerability of cortical projection neurons and spinal motor neurons, but without the presence of TDP-43 aggregates. Together with recent reports of mutations in another RNA binding protein (FUS/TLS) in familial ALS (14, 15), this supports that altered RNA-binding protein function (rather than toxic aggregation of TDP-43) likely plays a central and unexpected role in ALS pathogenesis.

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization

“…In addition, although premature sudden death prevented the assessment of cognitive function in previous studies using mutant TDP-43 transgenic animal models, cortical neuron degeneration has been consistently observed. 11,14,19,20,28 Therefore, our findings in hemizygous TDP-43 M337V mice do not necessarily contradict previous findings only reporting motor dysfunction in TDP-43 transgenic mice. Unlike other transgenic animal models showing increased expression of total TDP-43, the hemizygous TDP-43 M337V model does not demonstrate significantly changed expression of total TDP-43 in the brain and spinal cord, 29 indicating very low transgene expression.…”

“…[11][12][13][14][15][16][17][18][19][20] However, either premature death before the presence of full behavior impairments or extremely aggressive disease progression in many of these animal models make the interpretation of behavioral and neuropathological measurements, especially cognitive assessment, difficult. The TDP-43 M337V transgenic (Tg) mouse (i.e., Prnp-TARDBP* M337V; The Jackson Laboratory, stock no.…”

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

“…The analysis of lower MN functional activity is crucial to assess the effect of new treatments, because the loss of neuromuscular function is 1 of the hallmarks of the disease process in ALS animal models [29][30][31]. The results showed that PRE-084 administration significantly improved the amplitude of TA and plantar compound muscle action potential (CMAP), both in female and male SOD1 G93A mice from 12 weeks of age compared to untreated mice.…”

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

“…Deletion of TDP-43 is embryonically lethal, suggesting that dysregulation of RNA metabolism mediated through a TDP-43 defect probably contributes to the toxicity 20 . The TDP-43 mutant transgenic mice developed disease symptoms in the absence of cytoplasmic TDP-43 aggregates, which suggests that the loss-of-function of TDP-43 contributes to its pathogenesis 21 . On the other hand, overexpression of the fulllength or N-terminus-truncated TDP-43 in yeast is toxic and forms cytoplasmic aggregates 22 .…”