The protective effect of human platelet lysate in models of neurodegenerative disease: involvement of the Akt and MEK pathways.

Neurodegenerative diseases have huge economic and societal impacts, and place an immense emotional burden on patients and caregivers. Given that platelets have an essential physiological role in wound healing and tissue repair, human platelet lysates (HPLs) are being developed as a novel, effective biotherapy for neurodegenerative diseases. HPLs constitute abundant, readily accessible sources of physiological mixtures of many growth factors (GFs), with demonstrable effects on neuron survival and thus the development, maintenance, function and plasticity of the vertebrate nervous system. Here, we found that HPLs had marked neuroprotective abilities in cell-based models of Parkinson's disease and amyotrophic lateral sclerosis (the LUHMES and NSC-34 cell lines, respectively). The HPLs protected against specific cell death pathways (apoptosis and ferroptosis) and specific oxidative stress inducers [1-methyl-4-phenylpyridinium (MPP+) and menadione], and always afforded more protection than commonly used recombinant GFs (rGFs). The mechanism of protection of HPLs involved specific signalling pathways: whereas the Akt pathway was activated by HPLs under all conditions, the MEK pathway appeared to be more specifically involved in protection against MPP+ toxicity in LUHMES and, in a lesser extent, in staurosporine toxicity in NSC-34. Our present results suggest that HPLs-based therapies could be used to prevent neuronal loss in neurodegenerative diseases while overcoming the limitations currently associated with use of rGFs. Copyright © 2016 John Wiley & Sons, Ltd.

Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC.

Parkinson's disease (PD) is a complex illness characterized by progressive dopaminergic neuronal loss. Several mechanisms associated with the iron-induced death of dopaminergic cells have been described. Ferroptosis is an iron-dependent, regulated cell death process that was recently described in cancer. Our present work show that ferroptosis is an important cell death pathway for dopaminergic neurons. Ferroptosis was characterized in Lund human mesencephalic cells and then confirmed ex vivo (in organotypic slice cultures) and in vivo (in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model). Some of the observed characteristics of ferroptosis differed from those reported previously. For example, ferroptosis may be initiated by PKCα activation, which then activates MEK in a RAS-independent manner. The present study is the first to emphasize the importance of ferroptosis dysregulation in PD. In neurodegenerative diseases like PD, iron chelators, Fer-1 derivatives and PKC inhibitors may be strong drug candidates to pharmacologically modulate the ferroptotic signaling cascade.