Is A Treatment For Alzheimers and Parkinsons Within Grasp

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Is a Treatment for Alzheimers and Parkinsons Within Grasp?
by Deborah Grainger Last week our attention was turned to an article on the BBC News website, which hails one of the biggest discoveries in neurodegenerative disease research of 2013: scientists based at the University of Leicester, UK, may have f ound a way of stopping neurodegeneration in its tracks. It could mean that an ef f ective treatment f or diseases such as Alzheimers and Parkinsons are within reach. T he article ref ers to a paper published by Giovanna Malluccis lab in the journal Science Translational Medicine. It reports successful blockade of prion-disease progression by targeting the unfolded protein response (UPR) with an experimental compound. When given orally to prion-inf ected mice, the compound, a specif ic inhibitor of a key UPR kinase, prevented the emergence of clinical disease and the progression of neurodegeneration. T his builds on the labs previous work, published here in Nature, which showed that a build-up of misf olded proteins over-activates the UPR and shif ts cells towards protein production shutdown and an apoptotic f ate. Furthermore, the same Nature paper provided the initial evidence that targeting the UPR pathway, shif ting cells back towards protein production and not self -destruction, might be a usef ul strategy in preserving the integrity of neurons, despite the protein aggregation occurring within them. Protein aggregation and UPR over-activity are not just limited to prion diseases; they are a common f eature of other neurodegenerative conditions. T heref ore, the most exciting prospect of f ered by the work of the Mallucci lab is that of a universal treatment f or neurodegenerative disease, potentially applicable (but not limited to) Alzheimers, Parkinsons and Huntingtons. T he disease-causing culprits may be dif f erent in each case amyloid-beta accumulation in Alzheimers and alpha-synuclein in Parkinsons but their buildup results in the same def ense mechanisms being activated via the UPR. A treatment (or treatments) targeting this pathway would be a boon f or managing a vast array of dementias and wasting diseases; plus, paired with enhanced detection methods such treatment options could greatly reduce the burden these diseases put on healthcare systems worldwide. Bef ore that stage is reached, however, a lot more work is needed. T heres a long way to go f rom mouse to human, and one of the most important steps required is the development of a saf e, alternative drug; the compound of the current study comes with unwanted side ef f ects including weight loss and mild diabetes due to pancreatic damage. Prof essor Mallucci has appealed to the wider scientif ic community and pharmaceutical companies alike to help the design of therapeutic compounds that will saf ely target the UPR kinase identif ied in her labs latest study. Read related article Alzheimers breakthrough: Cure or hype? on the BBC News website.
More about t he UPR

Correct f olding of secreted and transmembrane proteins is f acilitated by several chaperone proteins in the endoplasmic reticulum (ER). Under physiological conditions the UPR operates as a protective mechanism, maintaining f olding homeostasis in the ER. It is induced in response to cellular and ERstress by dissociation of the molecular Re ad Alz he ime rs b re akthro ug h: Cure o r hyp e o n the BBC Ne ws we b s ite . (Imag e s o urc e : BBC Ne ws , SPL) chaperone GRP78/BiP f rom three proteins that initiate the UPR response: PERK, IRE1 and AFT 6. Stressors can take the f orm of amino acid deprivation, viral replication and, as the name suggests, the presence of unf olded proteins. T he UPR elicits its protective ef f ects through several actions, including: 1) Increasing chaperone protein expression to prevent protein aggregation and f acilitate correct protein f olding. T his can be induced by AFT 6 expression of XBP1 and subsequent splicing of XBP1 mRNA by IRE1a. 2) Reducing protein translation to lower the amount of proteins present in the ER. T his is initiated by phosphorylation of eukaryotic initiation f actor 2a (eIF2a) by PERK. GADD34 dephosphorylates eIF2a once the ER stress has been resolved and any unf olded proteins have been removed. Increases in PERK and eIF2 phosphorylation have been recorded in the brains of Alzheimers, Parkinsons, ALS (Lou Gherigs), and prion disease patients. 3) Stimulating lipid synthesis to increase ER volume.
4) And degrading unf olded proteins by activation of the ER-associated protein degradation (ERAD) pathway. Under conditions of prolonged stress, the goal of the UPR changes f rom one that promotes cellular survival to one that commits to apoptosis. On a small scale this last resort is protective, but such conditions develop on a larger scale in neurodegenerative disease, causing widespread damage. In its 2012 Nature paper the Mallucci lab showed that accumulation of misf olded prion protein in the brains of priondiseased mice caused such sustained overactivation of the PERK/eIF2 branch of the UPR that a critical decline in levels of key proteins, including synaptic proteins, occurs. Essentially, persistently high levels of phosphorylated eIF2 (eIF2-P) lead to neurodegeneration through sustained, uncompensated repression of protein synthesis. T he latest Mallucci lab study shows that by reversing the haitus on protein production by targeting the PERK-eIF2 branch of the UPR pharmacologically, the protective mechanisms of the UPR can be reinstated and protect neurons in conditions that would otherwise result in neurodegeneration.

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Is a Treatment for Alzheimers and Parkinsons Within Grasp?

More about t he UPR

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