Growth and Trophic Factors, pH and the Na+/H+ Exchanger in Alzheimers Disease, Other Neurodegenerative Diseases and Cancer: New Therapeutic Possibilities and Potential Dangers

Abstract

Abnormalities in the intricate intracellular signalling pathways play a key role in the deregulation of either spontaneous (normal or pathological) or induced (therapeutic) cell death mechanisms. Some of these pathways are increasingly becoming molecular therapeutic targets in different processes, ranging from neurodegenerative diseases to cancer. Recent discoveries in research and treatment have shown that failure to induce selective cell apoptosis in hyperproliferative processes, like neoplastic diseases, and the failure to prevent spontaneous cell death in neurodegenerative diseases (HNDDs) such as Alzheimer's disease (AD), multiple sclerosis (MS), amyothrophic lateral sclerosis (ALS), Huntington's disease (HD), and retinitis pigmentosa (RP), can be interpreted as problems stemming from the same basic mechanisms but moving in diametrically opposed directions. The integrated approach advanced here represents an interdisciplinary attempt to stimulate an integrated vision of two otherwise widely separated areas of research, experimental neurology and oncology. This kind of approach to the prevention of apoptosis (therapeutic antiapoptosis) and/or other forms of cell death in HNNDs, as well as to resistance to therapeutic apoptosis in cancer (pathological antiapoptosis), has the scope to improve the understanding of the dualistic nature of the basic abnormalities underlying the pathological deregulation of cell death. In this context, an intracellular pH (pH(i))-related approach to these opposed situations is advanced to provide a unified theory of the apoptosis-antiapoptosis machinery. Some potential therapeutic possibilities opened by these lines of research, regarding the utilization of human growth factors and/or cellular anti-acidification measures directed to sustain cellular acid-base homeostasis in different HNNDs are considered because of their potential therapeutic benefit. Finally, we advance some possible dangers and side-effects raised by these very same treatment efforts.

Mitochondrial translocation of α-synuclein is promoted by intracellular acidification

“…One common cellular response to a number of oxidative and metabolic challenges is a reduction of intracellular pH (pHi) [36,39,40]; this is likely an early and essential event during apoptosis and/or necrosis [41]. Mechanisms proposed for cytosolic acidification include: dysregulation of ion transport [42]; proton leakage from acidic organelles [43]; and hydrolysis of high energy nucleotides [44].…”

Ratiometric Imaging of pH Probes

“…Proton fluxes across membranes of intracellular organelles generate pH gradients that drive vesicle trafficking and posttranslational modification and sorting of cargo proteins (Marshansky & Futai, 2008;Rivinoja, Kokkonen, Kellokumpu, & Kellokumpu, 2006;Vavassori et al, 2013). Although in normal conditions proton fluxes are homeostatically controlled to maintain pHi and organelle pH within narrow physiological ranges, dysregulated proton fluxes enable many diseases and pathologies, including cancer (Cardone, Casavola, & Reshkin, 2005;Stock & Schwab, 2009;Webb et al, 2011), neurodegenerative disorders (Harguindey, Reshkin, Orive, Arranz, & Anitua, 2007), and a number of myopathies and cardiovascular dysfunctions (VaughanJones, Spitzer, & Swietach, 2009). Our current ability to measure dynamic and localized changes in pH within the cell is facilitated by new generations of pH-sensitive dyes and biosensors.…”

A Histidine Cluster in the Cytoplasmic Domain of the Na-H Exchanger NHE1 Confers pH-sensitive Phospholipid Binding and Regulates Transporter Activity

“…Most cancers have constitutively increased pH i of ϳ0.4 units, which enables proliferation and metastasis (2)(3)(4). Conversely, neurodegenerative disorders, including Parkinson's and Alzheimer's diseases, are associated with constitutively decreased pH i , which is predicted to enable tau and ␤-amyloid aggregation as well as cell death (5,6). Finely tuned pH i homeostasis is maintained by dynamic changes in ion transporter activity that is sensitive to intracellular proton concentrations.…”