Abstract
TAR DNA‐binding protein 43 (TDP‐43) has been implicated in frontotemporal lobar degeneration with ubiquitin‐positive inclusions (FTLD‐TDP) and amyotrophic lateral sclerosis. Histone deacetylase 1 (HDAC1) is involved in DNA repair and neuroprotection in numerous neurodegenerative diseases. However, the pathological mechanisms of FTLD‐TDP underlying TDP‐43 proteinopathies are unclear, and the role of HDAC1 is also poorly understood. Here, we found that aberrant cell cycle activity and DNA damage are important pathogenic factors in FTLD‐TDP transgenic (Tg) mice, and we further identified these pathological features in the frontal cortices of patients with FTLD‐TDP. TDP‐43 proteinopathies contributed to pathogenesis by inducing cytosolic mislocalization of HDAC1 and reducing its activity. Pharmacological recovery of HDAC1 activity in FTLD‐TDP Tg mice ameliorated their cognitive and motor impairments, normalized their aberrant cell cycle activity, and attenuated their DNA damage and neuronal loss. Thus, HDAC1 deregulation is involved in the pathogenesis of TDP‐43 proteinopathies, and HDAC1 is a potential target for therapeutic interventions in FTLD‐TDP.
Highlights
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two of the most common neurodegenerative diseases in early-onset populations
Our findings illuminate the role of Histone deacetylase 1 (HDAC1) in TAR DNA-binding protein 43 (TDP-43) proteinopathies and further support the hypothesis that restoring HDAC1 activity may be a feasible approach to treating FTLD-TDP and ALS
Quantified results from the frontal cortices indicated that the number of cells or neurons with aberrant cell cycle activity was significantly increased in FTLD-TDP Tg mice (Fig 1B) and strongly correlated with TDP-43 proteinopathies, since aberrant cell cycle activity cannot be detected without TDP-43 mislocalization at the age of 2 months of FTLD-TDP Tg mice (Fig EV1), which imply that TDP-43 proteinopathies precede the onset of cell cycle aberrance
Summary
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two of the most common neurodegenerative diseases in early-onset populations (age < 65 years). Histone acetylation further modulates important brain functions, including neuronal differentiation and memory formation In these critical aspects, histone deacetylases (HDACs) are regarded as essential regulators relevant to neurodegeneration. We previously generated an FTLD-TDP mouse model that overexpresses full-length TDP-43 in the forebrain under the control of the Ca2+/calmodulin-dependent kinase II promoter (Tsai et al, 2010) These mice progressively exhibit cognitive deficits starting from 2 months of age and motor dysfunction accompanied by the downregulation of several markers of neuronal plasticity, neuronal loss, and hippocampal atrophy by 6 months of age. Their TDP-43 proteinopathies progress with age and with the presence of cytosolic polyubiquitinated TDP-43 and 35- and 25-kDa TDP-43 fragments in urea-soluble fractions This model successfully mimics the pathogenesis of FTLD-TDP and can be used to investigate the mechanisms underlying neuronal death relevant to TDP-43 proteinopathies (Wang et al, 2012; Fang et al, 2014). Our findings illuminate the role of HDAC1 in TDP-43 proteinopathies and further support the hypothesis that restoring HDAC1 activity may be a feasible approach to treating FTLD-TDP and ALS
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