NPTX2 Involved in Neurodegeneration Driven by TDP-43 Aggregation

Altered, misfolded forms of TDP-43 are thought to contribute to neurodegeneration in a number of age-related conditions, primarily amyotrophic lateral sclerosis and frontotemporal dementia. As is the case for other misfolded proteins associated with neurodegeneration, aberrant TDP-43 may accumulate in much of the older population to levels sufficient to meaningfully contribute to cognitive decline. That TDP-43 has this negative impact is a relatively recent discovery, and in comparison to amyloid-β, tau, and α-synuclein little is known of the mechanisms by which TDP-43 aggregation causes dysfunction and death in brain cells. This doesn't stop the development of therapies that aim to clear forms of TDP-43, but it would be beneficial to have confirming data to demonstrate that the specific target is the right one.

In today's research materials, scientists report on a step forward in understanding how aggregated TDP-43 causes cell death. There are no well-proven animal models of TDP-43 aggregation, in part because some of the details of TDP-43 pathology involve mechanisms specific to the human version of the protein, so the researchers built cell models in order to explore changes in cell function induced by the presence of TDP-43. They found a good candidate for further exploration in the form of NPTX2, a synaptic protein that appears to be upregulated to toxic levels in neurons affected by TDP-43 aggregation. It remains to be seen as to how this finding will progress to the clinic in the absence of animal models of the condition.

Cracking the code of neurodegeneration: New model identifies potential therapeutic target

Despite the identification of the aberrant accumulation of a protein called TDP-43 in neurons in the central nervous system as a common factor in the vast majority of amyotrophic lateral sclerosis (ALS) and about half of frontotemporal dementia (FTD) patients, the underlying cellular mechanisms driving neurodegeneration remain largely unknown. Researchers have now developed a novel neural cell culture model called "iNets," derived from human induced pluripotent stem cells. The cultures lasted exceptionally long - up to a year - and were easily reproduced.

Employing the iNets model, the researchers identified a toxic accumulation of NPTX2, a protein normally secreted by neurons through synapses, as the missing link between TDP-43 misbehavior and neuronal death. To validate their hypothesis, they examined brain tissue from deceased ALS and FTD patients and indeed found that, also in patients, NPTX2 accumulated in cells containing abnormal TDP-43. This means that the iNets culture model accurately predicted ALS and FTD patient pathology. In additional experiments in the iNets model, the researchers tested whether NPTX2 could be a target for drug design to treat ALS and FTD. The team engineered a setup in which they lowered the levels of NPTX2 while neurons were suffering from TDP-43 misbehavior. They found that keeping NPTX2 levels low counteracted neurodegeneration in the iNets neurons.

A model of human neural networks reveals NPTX2 pathology in ALS and FTLD

Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies, which involve human-specific mechanisms that cannot be directly studied in animal models. Here, to explore the emergence and consequences of TDP-43 pathologies, we generated induced pluripotent stem cell-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors.

Overexpression of wild-type TDP-43 in a minority of neurons within iNets led to progressive fragmentation and aggregation of the protein, resulting in a partial loss of function and neurotoxicity. Single-cell transcriptomics revealed a novel set of misregulated RNA targets in TDP-43-overexpressing neurons and in patients with TDP-43 proteinopathies exhibiting a loss of nuclear TDP-43. The strongest misregulated target encoded the synaptic protein NPTX2, the levels of which are controlled by TDP-43 binding on its 3′ untranslated region. When NPTX2 was overexpressed in iNets, it exhibited neurotoxicity, whereas correcting NPTX2 misregulation partially rescued neurons from TDP-43-induced neurodegeneration. Notably, NPTX2 was consistently misaccumulated in neurons from patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby revealing a TDP-43-dependent pathway of neurotoxicity.

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