Cellular Maintenance Mechanisms Struggle to Break Down TDP-43 Aggregates, Leading to Neurodegeneration

The most common age-related neurodegenerative conditions are associated with the build up of various protein aggregates, chemically altered or misfolded proteins that can form solid deposits in and around cells when in that state. These protein aggregates are characterized by the ability to spread and grow, acting as seeds for more aggregation. They include the well known amyloid-β and tau of Alzheimer's disease, the α-synuclein associated with Parkinson's disease, and so forth. In recent years researchers have been devoting ever more effort to investigations of a less well known protein aggregate, TDP-43, associated with ALS and frontotemporal lobar degeneration. Today's open access paper is representative of work taking place to understand TDP-43 aggregates and how and why they form in the aging brain.

The goal of research into protein aggregates is to either find a way to remove them, or to find a way to prevent them from forming in the first place. Protein aggregation is a feature of old people, not young people, despite the fact that the mechanisms that can give rise to aggregation are present throughout life. Thus the damage and change of aging, the rising dysfunction in near all cellular processes, is in some way involved in allowing the presence of protein aggregates to rise to pathological levels. In the research here, the finger is pointed at age-related impairment of the cellular housekeeping systems of the proteasome and autophagy, both of which will break down excess TDP-43 when functioning correctly, at least up until a point.

Partial Failure of Proteostasis Systems Counteracting TDP-43 Aggregates in Neurodegenerative Diseases

Frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative diseases characterized by the mislocalization and cytosolic accumulation of the predominately nuclear TAR DNA-binding protein 43 (TDP-43) in the central nervous system. The presence of TDP-43 neuropathology in ~97% of ALS and ~50% of FTLD cases provides a molecular link, showing both diseases to be on the spectrum of the TDP-43 proteinopathies.

A number of physiological functions are perturbed in FTLD and ALS, including impaired protein homeostasis, RNA dysmetabolism, and reduced nucleocytoplasmic transport of mRNAs and proteins. The cytoplasmic deposition of TDP-43 occurs concomitantly with the depletion of native TDP-43 from the nucleus, causing neurodegeneration in both FTLD-U and ALS by a combination of gain-of-function (GOF) and loss-of-function (LOF) mechanisms. Cytosolic aggregates are known to be intrinsically toxic and able to recruit nuclear TDP-43, exacerbating their deleterious effects by contributing to the nuclear LOF.

In this scenario, it is crucial for neurons to maintain TDP-43 protein homeostasis by the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP). Indeed, a progressive decrease in the efficiency of both protein degradation systems has been reported as a major factor contributing to FTLD-U and ALS onset in aging patients. This hypothesis is also supported by genetic evidence, as many of the mutations associated with FTLD and ALS affect genes involved in UPS- or ALP-mediated degradation. Recent studies showed that the cytosolic accumulation of TDP-43 is turned-over mainly by the UPS, with ALP contributing to its degradation when TDP-43 accumulates as intractable aggregates.

Here we found an early ROS production and caspase-3 activation in murine neuroblastoma N2A cells, following cytosolic transfection with preformed inclusions of human TDP-43 in the absence of any recruitment of the nuclear TDP-43 reservoir. Moreover, our data identify mitochondria as the main responsible sites for the alteration of calcium homeostasis induced by TDP-43 aggregates, which, in turn, stimulates an increase in reactive oxygen species and, finally, caspase activation. We also showed that the UPS and ALP systems are unable to efficiently degrade at least a fraction of the TDP-43 inclusions in neurodegenerative diseases.

Comments

Following the link on TDP-43 I read this:

"TDP-43 has been shown to bind both DNA and RNA and have multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation. Recent work has characterized the transcriptome-wide binding sites revealing that thousands of RNAs are bound by TDP-43 in neurons."

And people still insist that messing with metabolism is a good approach...

Posted by: Antonio at August 16th, 2019 5:15 PM

Well, technically every medical treatment is "messing with metabolism". But I agree with what I think you mean, which is it's better to repair the underlying damage (the root causes) rather than trying to cure age-related conditions by treating the symptoms as if they were infectious diseases.

Posted by: Quinn at August 16th, 2019 7:18 PM

No, that is not what I say. What I say is that it's far better to remove the damage than to try to adjust tweak metabolism pathways so that the body responds better to that damage or generates less damage.

Posted by: Antonio at August 17th, 2019 1:49 AM

I came to think about something. Does those without body hair lives a bit a longer because it takes proteins to produce hair?

Posted by: gekki at August 17th, 2019 7:00 AM

And yet every damage approach to date has failed (i.e. amyloid drugs) or produced weak results (senolytics, stem cell monotherapies) in the clinic to date

There should be NO argument between the two poles - they are both going to be required at the end of the day to have any meaningful impact

Damage must be removed, but it can never be "stayed ahead of" so we're going to have to mess with it nonetheless

To promulgate one over the other is insanity and a path to the grave

Posted by: Fred Zobrisk at August 17th, 2019 9:43 AM

@Fred Zobrisk: Absolutely. A multipronged approach is literally the only one I can ever see succeeding.

Posted by: Dylan James Mah at August 17th, 2019 8:53 PM

"messing with metabolism" is the mantra some people use when their pet theory is challenged. The people who speak to those doing the actual research already know that the consensus is moving towards both repair and reprogramming as both are likely going to be needed. See Aubrey and Vadim's debate in Berlin + Aubreys further musings at our conference in NYC.

Posted by: Steve Hill at August 19th, 2019 4:58 AM

I thought so, Steve. It's good to have a medical researcher confirm it.

Posted by: Quinn at August 19th, 2019 6:37 AM

@Quinn, well I am a journalist not a researcher per se, and I base my opinion on what I am seeing and hearing when I speak to the researchers doing the actual work.

Posted by: Steve Hill at August 19th, 2019 10:59 AM

I know. What I meant was that you keep yourself educated on the latest research; not that you do the actual bench work. Sorry for the misunderstanding. :)

Posted by: Quinn at August 19th, 2019 11:02 AM

Fred Zobrisk:

Amyloid removal is only a small part of aging damage, only tiny part of it has been tried to been removed (i.e. A-beta) and it doesn't seem that the diseases it has been trialed have a single cause (you need to remove also tau, etc.).

No trial on senolytics on humans has finished yet, so pointing to failure is disingenous. Only one trial has finished phase 1 and it was only applied locally. We have only data on mice, and they didn't failed at all; on the contrary, they performed better than expected.

"they are both going to be required at the end of the day to have any meaningful impact"

You provided no argument for that. Simply sliding metabolism complexity under the carpet (and pretending there are no damages that the body can't eliminate) doesn't make such pathway-tweaking therapies useful or required.

"Damage must be removed, but it can never be "stayed ahead of" so we're going to have to mess with it nonetheless"

Nobody talked about "messing with damage" but "messing with metabolism". And there is no reason why we can't stay ahead of it. That's nonsense. If eliminated once, it can be eliminated again.

Posted by: Antonio at August 19th, 2019 3:20 PM

And the mantra is repeated and meanwhile, academia is already shifting towards a consensus beyond SENS that is based on both repair and rejuvenation via cellular reprogramming. The actual researchers are evolving their views based on the evidence, a pity some hardliners in the community are struggling to do the same.

Posted by: Steve Hill at August 19th, 2019 7:42 PM

The best that can be said about messing-with-metabolism is that it could continue to work as a crutch when damage-repair treatments first become available. However, once those treatments mature, MWM would no longer be needed.

The worst that can be said about messing-with-metabolism-besides the fact that there's little reason to think that it can prevent or cure anything-is that it directs resources away from the development of damage-repair approaches.

Academic consensus about medical research is a joke. Here's why:

1) Two decades late on senolytics
2) Got it wrong on ignoring tau tangles
3) Still has no idea about how to eliminate cancer
4) Mediocre commitment to immune system rejuvenation
5) Continues to ignore getting rid of crosslinks, lipofuscin, transthyretin, and atrial natriuretic peptide

Posted by: Florin at August 19th, 2019 9:25 PM

@Florin:

ANP relation to aging is new to me. Can you please point out to some introductory material?

Posted by: Antonio at August 20th, 2019 5:01 AM

and the hardliners continue to chant their mantra...

Posted by: Steve Hill at August 20th, 2019 5:02 AM

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