Decreased Hsp90 activity protects against TDP-43 neurotoxicity in a C. elegans model of amyotrophic lateral sclerosis.

Neuronal inclusions of hyperphosphorylated TDP-43 are hallmarks of disease for most patients with amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene coding for TDP-43, can cause some cases of familial inherited ALS (fALS), indicating dysfunction of TDP-43 drives disease. Aggregated, phosphorylated TDP-43 may contribute to disease phenotypes; alternatively, TDP-43 aggregation may be a protective cellular response sequestering toxic protein away from the rest of the cell.

Transcriptomic evaluation of tau and TDP-43 synergism shows tauopathy predominance and reveals potential modulating targets.

Alzheimer's disease (AD), the most common aging-associated neurodegenerative dementia disorder, is defined by the presence of amyloid beta (Aβ) and tau aggregates in the brain. However, more than half of patients also exhibit aggregates of the protein TDP-43 as a secondary pathology. The presence of TDP-43 pathology in AD is associated with increased tau neuropathology and worsened clinical outcomes in AD patients.

loss of function mutants protect against tau-driven shortened lifespan and hyperactive pharyngeal pumping in a model of tau toxicity.

Expression of human tau in neurons causes progressive, age-associated loss of motor coordination, selective neurodegeneration, and shortened lifespan. Loss of function (LOF) mutations in the conserved gene protects against progressive motor uncoordination and neurodegeneration in models of tauopathy. To determine whether LOF also protects against shortened lifespan of tau transgenic , we conducted lifespan assays comparing four different alleles of We found that LOF robustly suppresses the shortened lifespan of tau transgenic animals.

TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic Caenorhabditis elegans.

Although amyloid β (Aβ) and tau aggregates define the neuropathology of Alzheimer's disease (AD), TDP-43 has recently emerged as a co-morbid pathology in more than half of patients with AD. Individuals with concomitant Aβ, tau and TDP-43 pathology experience accelerated cognitive decline and worsened brain atrophy, but the molecular mechanisms of TDP-43 neurotoxicity in AD are unknown. Synergistic interactions among Aβ, tau and TDP-43 may be responsible for worsened disease outcomes.

Evaluation of Motor Impairment in C. elegans Models of Amyotrophic Lateral Sclerosis.

The neurodegenerative disease amyotrophic lateral sclerosis (ALS) features progressive loss of motor neurons accompanied by muscle weakness and motor impairment that worsens with time. While considerable advances have been made in determining genetic drivers of ALS for a subset of patients, the majority of cases have an unknown etiology. Further, the mechanisms underlying motor neuron dysfunction and degeneration are not well understood; therefore, there is an ongoing need to develop and characterize representative models to study these processes.

Resistance and resilience to Alzheimer's disease pathology are associated with reduced cortical pTau and absence of limbic-predominant age-related TDP-43 encephalopathy in a community-based cohort.

Alzheimer's disease neuropathologic change (ADNC) is defined by progressive accumulation of β-amyloid plaques and hyperphosphorylated tau (pTau) neurofibrillary tangles across diverse regions of brain. Non-demented individuals who reach advanced age without significant ADNC are considered to be resistant to AD, while those burdened with ADNC are considered to be resilient. Understanding mechanisms underlying ADNC resistance and resilience may provide important clues to treating and/or preventing AD associated dementia.

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation.

Detergent insoluble inclusions of TDP-43 protein are hallmarks of the neuropathology in over 90 % of amyotrophic lateral sclerosis (ALS) cases and approximately half of frontotemporal dementia (FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post-translationally modified, with phosphorylated TDP-43 (pTDP) being the most consistent and robust marker of pathological TDP-43 deposition. Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models.