On 2016 Dec 16, Claudiu Bandea commented:

Cell death by glutamine repeats: a revealing paradigm

(This comment was originally posted in Science on 4/4/2012: http://comments.sciencemag.org/content/10.1126/science.1219834)

In their perspective “Cell Death by Glutamine Repeats?,” Link and Saldi (1) expand on the suggestion made by Blum et al. (2) that the role of the polyglutamine-repeat protein PQN-41 in C. elegans nonapoptotic developmental cell death might be relevant for understanding the pathogenic mechanisms associated with Huntington’s disease (HD), Creutzfeldt-Jakob Disease (CJD) and other neurodegenerative diseases (NDs). HD is a progressive ND associated with an expansion of glutamine residues in the huntingtin protein (Htt), and CJD is one of the many fatal NDs associated with the prion protein (PrP), which has a domain rich in glutamine and asparagine (Q/N).

More remarkable, though, Link and Saldi bring forward a heretical concept: “glutamine-rich proteins could have a “natural role” in inducing cell death” (italics added). In other words, as recently proposed (3), the folding and assembly of these proteins into toxic agents that lead to cellular death and NDs are not inadvertent, protein misfolding events as they have been regarded for many decades, but evolutionarily selected properties and mechanisms associated with their biological function. Certainly, this is a radical departure from the current dogma that HD, CJD and many other NDs, including Alzheimer’s, Parkinson’s and ALS are protein misfolding diseases. If correct, as the current evidence indicates (3), this new hypothesis would lead to a major paradigm shift in understanding the etiology of these devastating diseases, which affect tens of millions of people worldwide, and the development of new preventive, diagnostic and therapeutic approaches.

Interestingly, similar to PQN-41, Htt is vital for embryonic development, and there is compelling evidence that it regulates the balance between cellular survival and death (4). There is also strong evidence that PrP, as well as other proteins implicated in NDs, such as Aβ, tau, and α-synuclein, can interfere with the life cycle of microbial and viral pathogens by various immune pathways, including apoptotic and nonapoptotic mechanisms for killing the host cells, which block their life cycle and limit the spread of infection (3). As suggested by Link and Saldi, PQN-4, Htt, PrP, TIA-1 and other Q/N-rich proteins (e.g. TDP-43 and FUS proteins, which are implicated in ALS and FTLD) can affect cellular viability by participating in the formation of cellular stress granules and bodies (5), which similar to other intrinsic cellular and developmental processes, such as RNA interference, might have been selected primarily as innate immune mechanisms (3).

References

(1) Link CD, Saldi TK. 2012. Cell death by glutamine repeats? Science 335:926; Link CD, 2012

(2) Blum ES et al. 2012. Control of nonapoptotic developmental cell death in Caenorhabditis elegans by a polyglutamine-repeat protein. Science 335:970-3; Blum ES, 2012

(3) Bandea CI. 2013. Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders. bioRxiv. doi: 10.1101/000604; http://biorxiv.org/content/biorxiv/early/2013/11/18/000604.full.pdf

(4) Zuccato C, Valenza M, Cattaneo E. 2010. Molecular mechanisms and potential therapeutical targets in Huntington's disease. Physiol. Rev. 90:905-81; Zuccato C, 2010

(5) Beckham CJ, Parker R. 2008. P bodies, stress granules, and viral life cycles. Cell Host Microbe 3:206-12; Beckham CJ, 2008

On 2016 Dec 16, Claudiu Bandea commented:

Cell death by glutamine repeats: a revealing paradigm

(This comment was originally posted in Science on 4/4/2012: http://comments.sciencemag.org/content/10.1126/science.1219834)

In their perspective “Cell Death by Glutamine Repeats?,” Link and Saldi (1) expand on the suggestion made by Blum et al. (2) that the role of the polyglutamine-repeat protein PQN-41 in C. elegans nonapoptotic developmental cell death might be relevant for understanding the pathogenic mechanisms associated with Huntington’s disease (HD), Creutzfeldt-Jakob Disease (CJD) and other neurodegenerative diseases (NDs). HD is a progressive ND associated with an expansion of glutamine residues in the huntingtin protein (Htt), and CJD is one of the many fatal NDs associated with the prion protein (PrP), which has a domain rich in glutamine and asparagine (Q/N).

More remarkable, though, Link and Saldi bring forward a heretical concept: “glutamine-rich proteins could have a “natural role” in inducing cell death” (italics added). In other words, as recently proposed (3), the folding and assembly of these proteins into toxic agents that lead to cellular death and NDs are not inadvertent, protein misfolding events as they have been regarded for many decades, but evolutionarily selected properties and mechanisms associated with their biological function. Certainly, this is a radical departure from the current dogma that HD, CJD and many other NDs, including Alzheimer’s, Parkinson’s and ALS are protein misfolding diseases. If correct, as the current evidence indicates (3), this new hypothesis would lead to a major paradigm shift in understanding the etiology of these devastating diseases, which affect tens of millions of people worldwide, and the development of new preventive, diagnostic and therapeutic approaches.

Interestingly, similar to PQN-41, Htt is vital for embryonic development, and there is compelling evidence that it regulates the balance between cellular survival and death (4). There is also strong evidence that PrP, as well as other proteins implicated in NDs, such as Aβ, tau, and α-synuclein, can interfere with the life cycle of microbial and viral pathogens by various immune pathways, including apoptotic and nonapoptotic mechanisms for killing the host cells, which block their life cycle and limit the spread of infection (3). As suggested by Link and Saldi, PQN-4, Htt, PrP, TIA-1 and other Q/N-rich proteins (e.g. TDP-43 and FUS proteins, which are implicated in ALS and FTLD) can affect cellular viability by participating in the formation of cellular stress granules and bodies (5), which similar to other intrinsic cellular and developmental processes, such as RNA interference, might have been selected primarily as innate immune mechanisms (3).

References

(1) Link CD, Saldi TK. 2012. Cell death by glutamine repeats? Science 335:926; Link CD, 2012

(2) Blum ES et al. 2012. Control of nonapoptotic developmental cell death in Caenorhabditis elegans by a polyglutamine-repeat protein. Science 335:970-3; Blum ES, 2012

(3) Bandea CI. 2013. Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders. bioRxiv. doi: 10.1101/000604; http://biorxiv.org/content/biorxiv/early/2013/11/18/000604.full.pdf

(4) Zuccato C, Valenza M, Cattaneo E. 2010. Molecular mechanisms and potential therapeutical targets in Huntington's disease. Physiol. Rev. 90:905-81; Zuccato C, 2010

(5) Beckham CJ, Parker R. 2008. P bodies, stress granules, and viral life cycles. Cell Host Microbe 3:206-12; Beckham CJ, 2008