The basis of clinicopathological heterogeneity in TDP-43 proteinopathy

Abstract

Transactive response DNA-binding protein 43 kDa (TDP-43) was identified as a major disease-associated component in the brain of patients with amyotrophic lateral sclerosis (ALS), as well as the largest subset of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), which characteristically exhibits cytoplasmic inclusions that are positive for ubiquitin but negative for tau and α-synuclein. TDP-43 pathology occurs in distinct brain regions, involves disparate brain networks, and features accumulation of misfolded proteins in various cell types and in different neuroanatomical regions. The clinical phenotypes of ALS and FTLD-TDP (FTLD with abnormal intracellular accumulations of TDP-43) correlate with characteristic distribution patterns of the underlying pathology across specific brain regions with disease progression. Recent studies support the idea that pathological protein spreads from neuron to neuron via axonal transport in a hierarchical manner. However, little is known to date about the basis of the selective cellular and regional vulnerability, although the information would have important implications for the development of targeted and personalized therapies. Here, we aim to summarize recent advances in the neuropathology, genetics and animal models of TDP-43 proteinopathy, and their relationship to clinical phenotypes for the underlying selective neuronal and regional susceptibilities. Finally, we attempt to integrate these findings into the emerging picture of TDP-43 proteinopathy, and to highlight key issues for future therapy and research.

Neurodegeneration-Associated Proteins in Human Olfactory Neurons Collected by Nasal Brushing

“…It is involved in various cellular processes, including apoptosis, cell division, and axonal transport. It is reported that in addition to being expressed in neurons, TDP-43 is abundantly expressed also in glia, as well as in many other cell types (Kawakami et al, 2019). TDP-43 immunostaining was detected in the nucleus.…”

CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges

“…In addition, FTD can be characterized pathologically by cellular inclusions of the transactive response DNA-binding protein 43 kDa (TDP-43) (Turner et al, 2017), a feature it shares with ALS, which is a distinct neurodegenerative disease affecting motor neurons in the brain and spinal cord. In fact, FTD and ALS appear to be on a spectrum and some patients display mixed phenotypes of both diseases (Kawakami et al, 2019). However, each disease also can present without involvement of the other one and unlike TDP-43, which is shared by both diseases, mutations in certain proteins are associated with either FTD or ALS, but not both.…”

C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease

“…Mutations in TARDBP are involved in about 4% of familial and 1% of sporadic ALS (sALS) cases. However, even wild-type TDP-43, while mostly nuclear in healthy cells, is cleaved and hyperphosphorylated and accumulates in ubiquitinated cytoplasmic aggregates in neurons of almost all ALS and about half of FTLD patients (reviewed in [100]). We tested if endogenous or overexpressed SMCR8 protein colocalizes with TDP-43 protein in cytoplasmic granules but found this not to be the case in unstressed or stressed U2OS or 2102Ep cells (Fig.…”