Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice

Abstract

IntroductionFrontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are characterized by the presence of ubiquitin-positive inclusions (1). These inclusions are found in the brain and spinal cord of ALS patients as well as in patients with a major subtype of FTLD designated FTLD-TDP because these inclusions were shown to be comprised of the TAR-DNA binding protein 43 (TDP-43) (2). Since (a) cognitive abnormalities or dementia consistent with FTLD are increasingly recognized in ALS patients, (b) some FTLD patients develop MND, and (c) cytoplasmic TDP-43 aggregates are found in the brain and spinal cord of both ALS and FTLD-TDP patients, TDP-43 pathology appears to define a single neurodegenerative disorder (TDP-43 proteinopathy) with a spectrum of clinical manifestations (3-5). The importance of TDP-43 in the pathogenesis of these diseases is supported by the presence of autosomal dominant mutations in the TARDBP gene associated with ALS and FTLD (6).Human TDP-43 (hTDP-43) is a highly conserved and ubiquitously expressed 414-amino acid nuclear protein that binds to both DNA and RNA (7,8). TDP-43 is implicated in repression of gene transcription, regulation of exon splicing, and nuclear body functions (for a summary see recent reviews, refs. 4 and 6). Pathological TDP-43 can be abnormally cleaved, phosphorylated, and ubiquitinated, and most TDP-43 aggregates are mislocalized outside the nucleus within the cytoplasm or neurites (2). Interestingly,

Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD

“…Thus, in progranulindeficient FTLD-TDP, nuclear depletion of TDP-43 and neurodegeneration can occur independent of cytoplasmic TDP-43 accumulation/aggregation. These results are consistent with observations that TDP-43, especially nuclear TDP-43, is required for neuron survival (Wegorzewska and Baloh, 2011;Igaz et al, 2011;Arnold et al, 2013).…”

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

“…At present, it is unclear whether neurodegeneration results from a loss of TDP-43 function in the nucleus or a toxic gain-offunction effect from cytosolic sequestration. The results from Tg mice expressing wild-type human and mouse TDP-43 are consistent with respect to the loss of nuclear TDP-43 but not cytoplasmic mislocalization 1,35,53,54 . In addition to generating aggregation-prone fragments, the cleavage of TDP-43's C-terminal disrupts binding to hnRNP A1, histone deacetylase 6 and fused in sarcoma/translocated in liposarcoma 2,55,56 .…”

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

“…[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.…”