Reviewing What is Known of TDP-43 Aggregation in Neurodegeneration

TDP-43 is one of the more recently discovered protein aggregates involved in neurodegenerative conditions. A few proteins in the body are capable of misfolding or otherwise becoming altered in ways that encourage other molecules of the same protein to do the same. Toxicity results, and it can spread as these altered proteins move from cell to cell. The condition most clearly associated with TDP-43 pathology is amyotrophic lateral sclerosis (ALS), but it appears to be involved in other forms of neurodegenerative disease as well. Researchers have made inroads into understanding how these aggregates form and disrupt normal cellular operations, but as yet little progress has been made towards development of a viable approach to therapy.

TAR DNA binding protein 43‚ÄČkDa (TDP-43) plays an important role in several essential cell functions. However, TDP-43 dysfunction has been implicated in the development of various brain diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Recent investigations into the individual components of TDP-43 pathology show how broader TDP-43 dysfunction may precede these disease end states, and therefore could help to explain why TDP-43 dysfunction continues to be implicated in a rapidly expanding category of neurodegenerative diseases.

TDP-43 pathology is usually characterized by insoluble, hyperphosphorylated and ubiquinated aggregates of TDP-43 in the cytoplasm, nucleus, and cell processes of neurons and glia. Mislocalization of TDP-43 within cellular compartments is also characteristic of the pathology. Normally TDP-43 is tightly auto-regulated and is almost entirely located in the nucleus. Consequently, depletion of TDP-43 in the nucleus, in association with abnormally high levels in the cytoplasm, is considered to be pathological. Indeed, TDP-43 mislocalization alone appears capable of causing mRNA instability, impaired gene regulation, mitochondrial dysfunction, impaired protein turnover, among other issues. However, the underlying causes of TDP-43 mislocalization and aggregation remain unclear.

The literature reviewed in this article suggests that dysregulation of TDP-43 initiated by some environmental and/or genetic insults can lead to a snowballing dysfunction across the cell, involving impaired gene expression, mRNA stability, as well as the function and coordination of those pathways directly regulated by TDP-43. Furthermore, the hallmarks of TDP-43 pathology, such as hyperphosphorylation and insoluble cytoplasmic accumulation of the protein may actually be artifacts of an upstream impairment in TDP-43's normal function.



could this be a potential target for cyclarity's cyclodextrins platform?

Posted by: erasmus at April 7th, 2023 6:11 AM
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