Could restoring cholesterol levels be a new therapeutic approach against TDP-43 proteopathies?

Two days ago the Rockefeller University Press published a public relation content stating that:

1. cholesterol metabolism may contribute to ALS and FTD
2. restoring cholesterol levels could be a new therapeutic approach for diseases associated with TDP-43.

These statements have been widely reproduced by the medical/vulgarization press.

This PR publication tells that cholesterol is associated with ALS.

"Our results ... suggest that defects in cholesterol metabolism may contribute to ALS and FTD, as well as other neurodegenerative diseases characterized by TDP-43 aggregates," Ling says.

There are bizarre statements in the scientific article that backs the PR publication. For example, the authors tell that TDP-43 is important for CNS health. Actually it is important for most types of cells, including muscle cells!

There is no clear hypothesis or leading idea explaining why the scientists started their work on a link between TDP-43 and cholesterol. The authors even state this in their article, which seems to nullify their own work:

Furthermore, knocking down TDP-43 appears to reduce global protein translation, which, at least in part, leads to reduced LDLR translation.

They started by performing RNA sequencing (RNA-seq) on the spinal cord RNA of mice models which have impaired TDP-43 expression in one case and impaired CNP1 expression, a gene involved in axonal support in Oligodendrocytes.

Then the authors used extensively GO enrichment, a dubious procedure which suggests new associations when the experiment do not present them. The GO ontology is itself often described as a low quality database describing unproved relations between molecules.

Among the many GO suggestions, the authors selected suggestions related to cholesterol metabolism.

Then they tried to verify these suggestions. They used many complex procedures, but I fail to understand their conclusions that TDP-43 is associated with cholesterol metabolism through SREBF2, because it seems at multiple times that they say in their own text that there is no such evidence. For example:

Although SREBF2 and HMGCR mRNA were reduced under TDP-43 knockdown conditions (Fig. S5 A), TDP-43 does not appear to alter the half-life of SREBF2, HMGCR, and LDLR mRNA (Fig. S5 B) or change the splicing pattern.

Afterward the authors tell that supplementation of cholesterol rescue the observed demyelination phenotype in TDP-43–deleted oligodendrocytes. But what they did was simply to observe in-vitro that the Myelin basic protein (a protein believed to be important in the process of myelination of nerves in the nervous system) was restored on oligodendrocytes cells.

They looked at 30 oligodendrocytes cells, which is certainly a tiny number. Furthermore neuron's axon is a complex assembly of many types of cells, isolating and observing a single type of cell in-vitro does not prove anything about their behavior in a living body.

Then they used organoids and cells from deceased patients. Double staining shown decreased HMGCR and HMGCS1 staining in white matter oligodendrocytes with TDP-43 inclusions when compared with nonaffected glial cells (arrows). HMGCR and HMGCS1 are enzymes controlling the metabolic pathway that produces cholesterol. But it is well known that stress granules are composed of many fragmented and misfolded proteins.

Conclusions

I see four conclusions:

1. While there was certainly a huge amount of work involved in this article, the text fails to describe this work as something deliberate, with some guiding ideas or hypotheses.
2. Once they decided there was some relation between TDP-43 and cholesterol, the authors certainly shown their willingness to prove their point, but never tried to invalidate their hypotheses. As they told themselves, TDP-43 interacts with thousand RNA. They did not show what is special in the relation between TDP-43 and cholesterol.
3. This work may have some interest in Alzheimer disease where we know since decades that cholesterol has a role (see Apolipoprotein gene) and that TDP-43 is involved in a fraction of the cases. It may have some interest in FTD or multiple sclerosis.
4. The relation of this work with ALS seems dubious. The hypothesis that ALS is related to demyelination was abandoned decades ago.
5. Cholesterol "supplementation" probably can't heal from ALS. The article did not prove anything in this area.

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