From the Guidelines
TDP-43 inclusions are a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), and their presence serves as an important biomarker for disease classification and potential therapeutic approaches. These inclusions form when the TDP-43 protein becomes mislocalized to the cytoplasm, undergoes modifications, and aggregates into insoluble clumps 1. The management of TDP-43 related diseases focuses on treating the underlying neurodegenerative condition with supportive care, symptom management, and disease-modifying therapies where available. For ALS patients, riluzole (50 mg twice daily) and edaravone (60 mg daily for 14 days, followed by a 14-day drug-free period) are FDA-approved treatments that may slow disease progression, though they don't directly target TDP-43 aggregation 1.
The presence of TDP-43 inclusions is observed in the majority of cases of hippocampal sclerosis (HS), about one-half of cases with FTLD and ubiquitin inclusions with or without motor neuron disease, most sporadic cases of amyotrophic lateral sclerosis, and commonly in cases with AD neuropathologic change or with LBD 1. It is essential to recognize that TDP-43 proteinopathy in these other neurodegenerative diseases is not always a primary event, and its clinical implications can vary depending on the context 1.
In terms of diagnosis, the presence of TDP-43 inclusions can be used to classify neurodegenerative diseases, and their detection can guide future therapeutic approaches as our understanding of protein misfolding diseases advances 1. However, it is crucial to consider the clinical phenotype and follow-up to determine the final diagnosis, especially in complex cases where TDP-43 inclusions may be present as a copathology 1.
Some key points to consider in the management of TDP-43 related diseases include:
- The importance of supportive care and symptom management
- The potential use of disease-modifying therapies where available
- The need for careful diagnosis and consideration of the clinical phenotype and follow-up
- The potential for TDP-43 inclusions to be present as a copathology in other neurodegenerative diseases
- The ongoing research into potential therapies targeting TDP-43 pathology 1.
Overall, the presence of TDP-43 inclusions is a critical aspect of neurodegenerative disease diagnosis and management, and their detection can provide valuable insights into the underlying pathology and potential therapeutic approaches.
From the Research
TDP-43 Inclusion
- TDP-43 inclusions are a hallmark of frontotemporal dementia-TDP (FTLD-TDP) and amyotrophic lateral sclerosis (ALS) 2
- The accumulation of TDP-43 in the cytoplasm of diseased neurons is a key feature of these diseases 2, 3
- TDP-43 mislocalization causes neurodegeneration through both loss and gain of function mechanisms, including disruption of pre-mRNA splicing and retrotransposon activation 3
Pathological Mechanisms
- The discovery of mutations in the TARDBP gene, which encodes TDP-43, has provided evidence for a link between TDP-43 alterations and neurodegeneration 2, 4
- TDP-43 proteinopathies represent a novel class of neurodegenerative disorders, akin to alpha-synucleinopathies and tauopathies 4
- Cytoplasmic re-localization of TDP-43 is a key event in the pathogenesis of ALS/FTD, and is regulated by non-canonical interactions with proteins such as 14-3-3θ 5
Therapeutic Strategies
- Restoring TDP-43 homeostasis represents a potential therapeutic strategy for ALS and FTD, and has been demonstrated in cell and animal models 6
- Small molecule-based therapies could be applied to modulate the mechanisms that lead to disrupted TDP-43 homeostasis, including protein homeostasis mechanisms such as clearance of pathological forms of TDP-43 6
- Gene therapy vectors targeting TDP-43 pathology have shown promise in mitigating functional deficits and neurodegeneration in ALS/FTD mouse models 5