Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence.

TDP-43 mislocalization and aggregation are key pathological features of motor neuron diseases (MND) including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, transgenic hTDP-43 WT or ΔNLS-overexpression animal models mainly capture late-stages TDP-43 proteinopathy, and do not provide a complete understanding of early motor neuron-specific pathology during pre-symptomatic phases. We have now addressed this shortcoming by generating a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43ΔNLS variant of mouse Tdp-43. This variant is either expressed conditionally in whole mice or specifically in the motor neurons. The mice exhibit loss of nuclear Tdp-43 concomitant with its cytosolic accumulation and aggregation in targeted cells, leading to increased DNA double-strand breaks (DSBs), signs of inflammation and DNA damage-associated cellular senescence. Notably, unlike WT Tdp43 which functionally interacts with Xrcc4 and DNA Ligase 4, the key DSB repair proteins in the non-homologous end-joining (NHEJ) pathway, the Tdp-43ΔNLS mutant sequesters them into cytosolic aggregates, exacerbating neuronal damage in mice brain. The mutant mice also exhibit myogenic degeneration in limb muscles and distinct motor deficits, consistent with the characteristics of MND. Our findings reveal progressive degenerative mechanisms in motor neurons expressing endogenous Tdp-43ΔNLS mutant, independent of TDP-43 overexpression or other confounding etiological factors. Thus, this unique Tdp-43 KI mouse model, which displays key molecular and phenotypic features of Tdp-43 proteinopathy, offers a significant opportunity to further characterize the early-stage progression of MND and also opens avenues for developing DNA repair-targeted approaches for treating TDP-43 pathology-linked neurodegenerative diseases.

RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.

TDP43 is an RNA/DNA binding protein increasingly recognized for its role in neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to the formation of detrimental cytosolic aggregates and a reduction in nuclear functionality within neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expressions. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.

Tropical myeloneuropathies: a new aetiology

Tropical myeloneuropathies are a group of neurological disorders known to occur in subtropical and tropical regions. Many aetiologies have been postulated and investigated over the past 100 years, but no single cause has been found. Recent studies suggest that human T-cell lymphotropic virus HTLV-I is the causative agent of one of these tropical myeloneuropathies, endemic tropical spastic paraparesis, and of a related disorder in southern Japan called HTLV-I-associated myelopathy. Endemic tropical spastic paraparesis is now being reported from geographical and climatic regions that were previously thought to be free of these disorders. (AU)

Human T-lymphotropic virus type 1: a retrovirus causing chronic myeloneuropathies in tropical and temperate climates

Human T-cell lymphotropic virus type I (HTLV-I), the first human retrovirus to be isolated, is the cause of endemic tropical spastic paraparesis (TSP). Originally, this chronic neurological disorder was described as a disease seen among blacks of low socioeconomic status living in tropical countries, and thus for many decades TSP remained a little known curiousty outside the endemic regions. The link between HTLV-I infection and TSP was made fortuitously, when antibodies to HTLV-I were found in serum and cerebrospinal fluid of TSP patients in Jamaica, Colombia, and Martinique. Soon thereafter a similar disorder, designated HTLV-I associated myelopathy (HAM), was reported from southern Japan. This broadened the geographic and ethnic boundaries of this chronic myelopathy and the disease has now been reported in multiple ethnic groups from more than 40 countries, in both tropical and temperate regions. The name TSP/HAM is now used to include all patients (regardless of race or country of origin) who have HTLV-I-positive endemic TSP or HAM. (AU)

The role of HTLV-I in tropical spastic paraparesis in Jamaica

We report clinical and laboratory investigations of 47 native-born Jamaican patients with endemic tropical spastic paraparesis and of 1 patient with tropical ataxic neuropathy. Mean age at onset was 40 years, with a female-male preponderance (2.7:1). Neurological features of endemic tropical spastic paraparesis are predominantly those of a spastic paraparesis with variable degrees of proprioceptive and/or superficial sensory impairment. Using enzyme-linked immunoabsorbent assay (ELISA), IgG antibodies to human T-lymphotropic virus type I (HTLV-I) were present in 82 percent of sera and 77 percent of cerebrospinal fluids. On Westren blot analysis, IgG antibodies detected the p19 and p24 gag-encoded core proteins in both serum and cerebrospinal fluid. Titers were tenfold higher by ELISA in serum than in cerebrospinal fluid, and some oligoclonal bands present in fluid were not seen in serum . Serum-cerebrospinal fluid albumin ratios wer normal, and IgG indexes indicated intrathecal IgG synthesis. Histopathological changes showed a chronic inflammatry reaction with mononuclear cell infiltration, perivascular cuffing, and demyelination that was predominant in the lateral colmns. In 1 patient, a retrovirus morphologically similar to HTLV-I on electron microscopy was isolated from spinal fluid. Our investgations show that endemic tropical spastic paraparesis in Jamaica is a retrovirus-assiciated myelopathy and that HTLV-I or an antigenically similar retrovirus is the causal agent. (AU)