There are many questions about how TDP-43 can be deleterious in ALS disease. Normally TDP-43 is involved in many repairing or protecting scenarios. In 2013 scientists proposed that misplaced TDP-43 was killing mitochondria, by disturbing their fission/fusion processes (mitochondria are very dynamic structures). However this is not the scientific consensus.
A scientific article published on October 30, 2019 about Alzheimer's disease confirms the effect of a peptide against the aggregation of TDP-4 in mitochondria. This peptide and others were already described in a 2016 ALS publication.
The molecular mechanisms by which TDP-43 contributes to the pathology of ALS remained elusive. In the 2016 article, the authors wrote that they found that TDP-43 accumulated in neuronal mitochondria in subjects with ALS or frontotemporal dementia. Neurodegenerative diseases are characterized by cytoplasmic localization of TDP-43 in granule types. The 2016 study directly linked the toxicity of TDP-43 to mitochondrial metabolism and proposed targeting the mitochondrial localization of TDP-43 as a promising therapeutic approach for ALS.
The authors of the 2019 study (Gao et al.), demonstrate that one of the two mitochondrial TDP-43 inhibitory peptides of the 2016 article, when administered late in the course of the disease, may attenuate the development and progression of cerebral neuronal loss and behavioral deficits in the 5XFAD transgenic mouse model in Alzheimer's disease.
If this peptide is effective against TDP-43 proteinopathies, it is a real breakthrough because a peptide is something that is easy to produce at a low cost.
In neurodegenerative diseases, TDP-43 is localized in the cytoplasm as well as in mitochondria that may be free in the cytoplasm or anchored in the endoplasmic reticulum, where it gives it the "raw" appearance of the endoplasmic reticulum.
TDP-43 or truncated forms of TDP-43 may be present inside or outside the mitochondria. The portion of the total length of TDP-43 within the mitochondria can bind to the subunits encoding the mitochondria-mediated messenger RNA (mRNA), whereas the truncated TDP-43 lacks the locating sequence. mitochondrial M1 is limited to the inner membrane space no effect on ND3 / 6 expression or mitochondrial function.
The mitochondrial localization of TDP-43 is dependent on its M1 motif, the deletion of which suppresses its mitochondrial accumulation. The PM1 synthesized peptide (YGRKKRRQRRRAQFPGACGL) in which the M1 motif was fused to the TAT peptide (GRKKRRQRRR), competitively inhibits the mitochondrial localization of TDP-43 and suppresses the TDP-43 induced toxicity on mitochondria.
The authors used PM1, a peptidic inhibitor derived from TDP-43, as a continuous injection, to specifically reduce its expression in mitochondria. PM1 abolished TDP-43 protein kinetics, reversed neuronal loss, and reduced neuroinflammation in aged 5XFAD mice long after symptom onset. Since the amyloid plaque load was not attenuated or prevented by PM1, the authors' results clearly indicate that TDP-43 in mitochondria does not affect the pathology of Aβ.
Chronic administration of the PM1 peptide significantly attenuated TDP-43 protein kinetics, mitochondrial abnormalities, microgliosis, and even neuronal loss, but was without effect on amyloid plaque load in 12-month-old 5XFAD mice well after the onset of symptoms. PM1 also improved cognitive and motor functions in 12-month-old 5XFAD mice and completely prevented the development of mild cognitive impairment in 6-month-old 5XFAD mice.
Beyond its involvement in Alzheimer's disease, this article corroborates the 2016 article on ALS and therefore offers hope that a continuous (insulin pump-like) delivery of a low-cost peptide could to be very beneficial for ALS.
This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.