Neurodegenerative Diseases: Regenerative Mechanisms and Novel Therapeutic Approaches

Abstract

Regeneration refers to regrowth of tissue in the central nervous system. It includes generation of new neurons, glia, myelin, and synapses, as well as the regaining of essential functions: sensory, motor, emotional and cognitive abilities. Unfortunately, regeneration within the nervous system is very slow compared to other body systems. This relative slowness is attributed to increased vulnerability to irreversible cellular insults and the loss of function due to the very long lifespan of neurons, the stretch of cells and cytoplasm over several dozens of inches throughout the body, insufficiency of the tissue-level waste removal system, and minimal neural cell proliferation/self-renewal capacity. In this context, the current review summarized the most common features of major neurodegenerative disorders; their causes and consequences and proposed novel therapeutic approaches.

Keywords: intra-cellular signaling; mechanisms; neurogenesis; neuroregeneration; therapeutics.

Figure 1

Major Neurodegenerative diseases, their associated regions, and current therapeutic interventions. Left panel: Brain disorders are color and shown in representative areas of the brain. Right panel: current pharmacological treatments and their areas of activity within the brain. Abbreviations: Basal ganglion (BG), Brain Stem (BS), Cerebellum (Crbl), Corpus callosum (CC), Cortex (Cx), Hippocampus (Hp), Striatum (St), Substantia Nigra (SN).

Figure 2

The interplay of neurotrophic factors, steroids, and intra-cellular signaling, in growth and differentiation of neural tissue. Cells sense different cues in the extracellular environment through membranous receptors, and these changes are communicated downstream through cascades of protein/cytoplasmic factor activation and inactivation. Many of these changes go through Protein kinase B or AKT, and mammalian target of rapamycin (mTOR), which further stimulate ribosomal proteins, i.e., 4EBP and S6 kinases, as well as PKC and SG1K. Stimulation of ribosomal proteins leads to protein synthesis, proliferation, growth, and differentiation; whilst PKC and SGK1 activation suppresses apoptotic pathways and improves survival. Abbreviations: BDNS (brain-derived neurotrophic factor), NT3 (Netrins 3), TGF (transforming growth factor), NGF (nerve growth factor), EGF (epithelial growth factor), CTNF (ciliary neurotrophic factor), GPCR (G protein-coupled receptor), Pi3K (phosphoinositide 3 kinase), Akt (protein kinase b), mTORC1 (mammalian target of rapamycin complex1), mTORC2 (mammalian target of rapamycin complex 2), 4EBP (eukaryotic initiation factor 4 binding protein), S6K (ribosomal protein S6 kinase), PKC (protein kinase c), SGK1 (glucocorticoid regulated kinase 1).